Determination Of Tgf-beta Pathway Activity Using Unique Combination Of Target Genes

Abstract

A bioinformatics process which provides an improved means to detect TGF-.beta. cellular signaling pathway in a subject, such as a human, based on the expression levels of one or more unique target gene(s) of the TGF-.beta. cellular signaling pathway measured in a sample. The invention includes an apparatus comprising a digital processor configured to perform such a method, a non-transitory storage medium storing instructions that are executable by a digital processing device to perform such a method, and a computer program comprising program code means for causing a digital processing device to perform such a method. Kits are also provided for measuring expression levels of unique sets of TGF-.beta. cellular signaling pathway target genes.

Description

RELATED APPLICATIONS

[0001] This application claims the benefit of European Patent Application No. EP14190270.0, filed Oct. 24, 2014, the entirety of the specification and claims thereof is hereby incorporated by reference for all purposes.

INCORPORATION-BY-REFERENCE OF MATERIAL SUBMITTED ON AS A TEXT FILE VIA THE OFFICE ELECTRONIC FILING SYSTEM (EFS-WEB)

[0002] A Sequence Listing associated with this application is provided in text format in lieu of a paper copy, and is hereby incorporated by reference into the specification. The name of the text file containing the Sequence Listing is 2014PF00582_2015-10-26_sequencelisting_ST25.txt. The text file is 295 KB, was created on Oct. 26, 2015, and is being submitted electronically via EFS-Web.

FIELD OF THE INVENTION

[0003] The present invention is in the field of systems biology, bioinformatics, genomic mathematical processing and proteomic mathematical processing. In particular, the invention includes a systems-based mathematical process for determining the activity of a TGF-.beta. cellular signaling pathway in a subject based on expression levels of a unique set of selected target gene(s) in a subject. The invention further provides an apparatus that includes a digital processor configured to perform such a method, a non-transitory storage medium storing instructions that are executable by a digital processing device to perform such a method, and a computer program comprising a program code means for causing a digital processing device to perform such a method. The present invention also includes kits for the determination of expression levels of the unique combinations of target genes.

BACKGROUND OF THE INVENTION

[0004] As knowledge of tumors including cancers evolve, it becomes more clear that they are extraordinarily heterogeneous and multifactorial. Tumors and cancers have a wide range of genotypes and phenotypes, they are influenced by their individualized cell receptors (or lack thereof), micro-environment, extracellular matrix, tumor vascularization, neighboring immune cells, and accumulations of mutations, with differing capacities for proliferation, migration, stem cell properties and invasion. This scope of heterogeneity exists even among same classes of tumors. See generally: Nature Insight: Tumor Heterogeneity (entire issue of articles), 19 Sep. 2013 (Vol. 501, Issue 7467); Zellmer and Zhang, "Evolving concepts of tumor heterogeneity", Cell and Bioscience 2014, 4:69.

[0005] Traditionally, physicians have treated tumors, including cancers, as the same within class type (including within receptor type) without taking into account the enormous fundamental individualized nature of the diseased tissue. Patients have been treated with available chemotherapeutic agents based on class and receptor type, and if they do not respond, they are treated with an alternative therapeutic, if it exists. This is an empirical approach to medicine.

[0006] There has been a growing trend toward taking into account the heterogeneity of tumors at a more fundamental level as a means to create individualized therapies, however, this trend is still in its formative stages. What is desperately needed are approaches to obtain more metadata about the tumor to inform therapeutic treatment in a manner that allows the prescription of approaches more closely tailored to the individual tumor, and perhaps more importantly, avoiding therapies destined to fail and waste valuable time, which can be life-determinative.

[0007] A number of companies and institutions are active in the area of classical, and some more advanced, genetic testing, diagnostics, and predictions for the development of human diseases, including, for example: Affymetrix, Inc.; Bio-Rad, Inc; Roche Diagnostics; Genomic Health, Inc.; Regents of the University of California; Illumina; Fluidigm Corporation; Sequenom, Inc.; High Throughput Genomics; NanoString Technologies; Thermo Fisher; Danaher; Becton, Dickinson and Company; bioMerieux; Johnson & Johnson, Myriad Genetics, and Hologic.

[0008] Several companies have developed technology or products directed to gene expression profiling and disease classification. For example, Genomic Health, Inc. is the assignee of numerous patents pertaining to gene expression profiling, for example: U.S. Pat. Nos. 7,081,340; 8,808,994; 8,034,565; 8,206,919; 7,858,304; 8,741,605; 8,765,383; 7,838,224; 8,071,286; 8,148,076; 8,008,003; 8,725,426; 7,888,019; 8,906,625; 8,703,736; 7,695,913; 7,569,345; 8,067,178; 7,056,674; 8,153,379; 8,153,380; 8,153,378; 8,026,060; 8,029,995; 8,198,024; 8,273,537; 8,632,980; 7,723,033; 8,367,345; 8,911,940; 7,939,261; 7,526,637; 8,868,352; 7,930,104; 7,816,084; 7,754,431 and 7,208,470, and their foreign counterparts.

[0009] U.S. Pat. No. 9,076,104 to the Regents of the University of California titled "Systems and Methods for Identifying Drug Targets using Biological Networks" claims a method with computer executable instructions by a processor for predicting gene expression profile changes on inhibition of proteins or genes of drug targets on treating a disease, that includes constructing a genetic network using a dynamic Bayesian network based at least in part on knowledge of drug inhibiting effects on a disease, associating a set of parameters with the constructed dynamic Bayesian network, determining the values of a joint probability distribution via an automatic procedure, deriving a mean dynamic Bayesian network with averaged parameters and calculating a quantitative prediction based at least in part on the mean dynamic Bayesian network, wherein the method searches for an optimal combination of drug targets whose perturbed gene expression profiles are most similar to healthy cells.

[0010] Affymetrix has developed a number of products related to gene expression profiling. Non-limiting examples of U.S. patents to Affymetrix include: U.S. Pat. Nos. 6,884,578; 8,029,997; 6,308,170; 6,720,149; 5,874,219; 6,171,798; and 6,391,550.

[0011] Likewise, Bio-Rad has a number of products directed to gene expression profiling. Illustrative examples of U.S. patents to Bio-Rad include: U.S. Pat. Nos. 8,021,894; 8,451,450; 8,518,639; 6,004,761; 6,146,897; 7,299,134; 7,160,734; 6,675,104; 6,844,165; 6,225,047; 7,754,861 and 6,004,761.

[0012] Koninklijke Philips N.V. (NL) has filed a number of patent applications in the general area of assessment of cellular signaling pathway activity using various mathematical models, including U.S. Ser. No. 14/233,546 (WO 2013/011479), titled "Assessment of Cellular Signaling Pathway Using Probabilistic Modeling of Target Gene Expression"; U.S. Ser. No. 14/652,805 (WO 2014/102668) titled "Assessment of Cellular Signaling Pathway Activity Using Linear Combinations of Target Gene Expressions; WO 2014/174003 titled "Medical Prognosis and Prediction of Treatment Response Using Multiple Cellular Signaling Pathway Activities; and WO 2015/101635 titled "Assessment of the PI3K Cellular Signaling Pathway Activity Using Mathematical Modeling of Target Gene Expression.

[0013] Despite this progress, more work is needed to definitively characterize tumor cellular behavior. In particular, there is a critical need to determine which pathways have become pathogenic to the cell. However, it is difficult to identify and separate abnormal cellular signaling from normal cellular pathway activity.

[0014] Transforming growth factor-.beta. (TGF-.beta.) is a cytokine that controls various functions in many cell types in humans, such as proliferation, differentiation, and wound healing. In pathological disorders, such as cancer (e.g., colon, breast, prostate), the TGF-.beta. cellular signaling pathway can play two opposing roles, either as a tumor suppressor or as a tumor promoter. TGF-.beta. may act as a tumor suppressor in the early phases of cancer development, however in more progressed cancerous tissue TGF-.beta. can act as a tumor promoter by acting as a regulator of invasion and metastasis (see Padua D. and Massague J., "Roles of TGF-.beta. in metastasis", Cell Research, Vol. 19, No. 1, 2009, pages 89 to 102).

[0015] TGF-.beta. exists in three isoforms (gene names: TGF-.beta.1, TGF-.beta.2, TGF-.beta.3). It is secreted as an inactive precursor homodimeric protein, which is known to be increased in cancer cells compared to their normal counterparts (see Massague J., "How cells read TGF-.beta. signals", Nature Reviews Molecular Cell Biology, Vol. 1, No. 3, 2000, pages 169 to 178).

[0016] The TGF-.beta. precursor can be proteolytically activated, after which it binds to an extracellular TGF-.beta. receptor that initiates an intracellular "SMAD" signaling pathway. Various SMAD proteins (receptor-regulated or R-SMADs (SMAD 1, 2, 3, 5 and 8) and SMAD4) form a heterocomplex that enters the nucleus where it acts as a transcription factor, inducing the expression of a range of proteins which affect tumor growth (see FIG. 1; L. TGF-.beta.=Latent TGF-.beta.; PR=Proteasome; PH=Phosphatase; Co--R.dbd.Co-repressors; Co-A=Co-activators). The term "TGF-.beta. cellular signaling pathway" herein refers to a signaling process triggered by TGF-.beta. binding to the extracellular TGF receptor causing the intracellular SMAD cascade, which ultimately leads to the formation of a SMAD complex that acts as a transcription factor.

[0017] A number of anti-TGF-.beta. therapies are in preclinical or clinical development (see Yingling J. M. et al., "Development of TGF-.beta. signaling inhibitors for cancer therapy", Nature Reviews Drug Discovery, Vol. 3, No. 12, 2004, pages 1011 to 1022; Nacif and Shaker, "Targeting Transforming Growth Factor-B (TGF-.beta.) in Cancer and Non-Neoplastic Diseases"; Journal of Cancer Therapy, 2014, 5, 735-747).

[0018] However, physicians must use caution in administering an anti-TGF-.beta. drug to a patient with a tumor, including cancer, because in some tumors, TGF-.beta. is playing a tumor suppressing role. It is therefore important to be able to more accurately assess the functional state of the TGF-.beta. cellular signaling pathway at specific points in disease progression. For example, the TGF-.beta. cellular signaling pathway, with respect to cancer, is more likely to be tumor-promoting in its active state and tumor-suppressing in its passive state. Notwithstanding, it can be difficult to discern the difference in a diseased cell.

[0019] It is therefore an object of the invention to provide a more accurate process to determine the tumorigenic propensity of the TGF-.beta. cellular signaling pathway in a cell, as well as associated methods of therapeutic treatment, kits, systems, etc.

SUMMARY OF THE INVENTION

[0020] The present invention includes methods and apparatuses for determining the activity level of a TGF-.beta. cellular signaling pathway in a subject, typically a human with diseased tissue such as a tumor or cancer, wherein the activity level of the TGF-.beta. cellular signaling pathway is determined by calculating a level of TGF-.beta. transcription factor element in a sample of the involved tissue isolated from the subject, wherein the level of the TGF-.beta. transcription factor element in the sample are determined by measuring the expression levels of a unique set of target genes controlled by the TGF-.beta. transcription factor element using a calibrated pathway model that compares the expression levels of the target genes in the sample with expression levels of the target genes in the calibrated pathway model.

[0021] In particular, the unique set of target genes whose expression level is analyzed in the model includes at least three target genes, at least four target genes, at least five target genes, at least six target genes, at least seven target genes, at least eight target genes, at least nine target genes, at least ten target genes or more selected from ANGPTL4, CDC42EP3, CDKN1A, CDKN2B, CTGF, GADD45A, GADD45B, HMGA2, ID1, IL11, SERPINE1, INPP5D, JUNB, MMP2, MMP9, NKX2-5, OVOL1, PDGFB, PTHLH, SGK1, SKIL, SMAD4, SMAD5, SMAD6, SMAD7, SNAIL SNAI2, TIMP1, and VEGFA. In one embodiment, the unique set of target genes whose expression level is analyzed in the model includes ANGPTL4 and CDC42EP3, and at least one or more, for example, two, three, four, five, six, seven or more of CDKN1A, CTGF, GADD45A, GADD45B, HMGA2, ID1, IL11, SERPINE1, JUNB, PDGFB, PTHLH, SGK1, SKIL, SMAD4, SMAD5, SMAD6, SMAD7, SNAI2, and VEGFA. In one embodiment, the unique set of target genes is ANGPTL4 and CDC42EP3, and at least one or more, for example, two, three, four, five, six, seven, eight, nine, or ten target genes selected from CDKN1A, CTGF, GADD45B, ID1, IL11, JUNB, PDGFB, SKIL, SMAD7, and SNAI2. In one embodiment, the unique set of target genes is ANGPTL4 and CDC42EP3, and at least one or more, for example, two, three, four, five, six, seven, eight, nine, or ten of target genes selected from CDKN1A, CTGF, GADD45B, ID1, SERPINE1, JUNB, VEGFA, SKIL, SMAD7, and SNAI2. In one embodiment, the target genes analyzed include at least ANGPTL4, CDC42EP3, ID1, SERPINE1, JUNB, SKIL, and SMAD7.

[0022] Using this invention, health care providers will be able to more accurately assess the functional state of the TGF-.beta. cellular signaling pathway at specific points in disease progression. Without being bound by any particular theory, it is believed that the identified target genes of the present invention in combination with the analytical methods described herein reduces the noise associated with the use of large subsets of target genes as previously described in the literature. Furthermore, as described and exemplified below, the use of specific combinations of select target genes allows for the precise determination of cellular signaling activity, and allows for an increased accuracy in the determination of disease state and prognosis. Accordingly, such cellular signaling pathway status can be used to, for example but not limited to, identify the presence or absence of disease and/or particular disease state or advancement, identify the presence or absence of a disorder or disease state, identify a particular subtype within a disease or disorder based one the activity level of the TGF-.beta. cellular signaling pathway, derive a course of treatment based on the presence or absence of TGF-.beta. signaling activity for example by administering a TGF-.beta. inhibitor, and/or monitor disease progression in order to, for example, adjust therapeutic protocols based on a predicted drug efficacy in light of the determined activity of the TGF-.beta. cellular signaling pathway in the sample.

[0023] The term "TGF-.beta. transcriptional factor element" or "TGF-.beta. TF element" or "TF element" refers to either a protein or protein complex transcriptional factor triggered by the binding of TGF-.beta. to its receptor or an intermediate downstrean signaling agent between the binding of TGF-.beta. to its receptor and the final transcriptional factor protein or protein complex. It is known that TGF-.beta. binds to an extracellular TGF-.beta. receptor that initiates an intracellular "SMAD" signaling pathway and that various SMAD proteins (receptor-regulated or R-SMADs (SMAD 1, 2, 3, 5 and 8) and SMAD4) can form a heterocomplex.

[0024] The present invention is based on the realization of the inventors that a suitable way of identifying effects occurring in the TGF-.beta. cellular signaling pathway can be based on a measurement of the signaling output of the TGF-.beta. cellular signaling pathway, which is--amongst others--the transcription of the unique target genes described herein by a TGF-.beta. transcription factor (TF) element controlled by the TGF-.beta. cellular signaling pathway. This realization by the inventors assumes that the TF level is at a quasi-steady state in the sample which can be detected by means of--amongst others--the expression values of the target genes. The TGF-.beta. cellular signaling pathway targeted herein is known to control many functions in many cell types in humans, such as proliferation, differentiation and wound healing. Regarding pathological disorders, such as cancer (e.g., colon, pancreatic, lung, brain or breast cancer), the TGF-.beta. cellular signaling pathway plays two opposite roles, either as a tumor suppressor or as a tumor promoter, which is detectable in the expression profiles of the target genes and thus exploited by means of a mathematical model.

[0025] The present invention makes it possible to determine the activity level of the TGF-.beta. cellular signaling pathway in a subject by (i) determining a level of a TGF-.beta. TF element in a sample from the subject, wherein the determining is based at least in part on evaluating a mathematical model relating expression levels of one or more target gene(s) of the TGF-.beta. cellular signaling pathway, the transcription of which is controlled by the TGF-.beta. TF element, to the level of the TGF-.beta. TF element, and by (ii) calculating the activity of the TGF-.beta. cellular signaling pathway in the subject based on the determined level of the TGF-.beta. TF element in the sample of the subject. In certain embodiments, the calculated activity level of the TGF-.beta. cellular signaling pathway is indicative of an active TGF-.beta. cellular signaling pathway. This, for example, allows improving the possibilities of characterizing subjects that have a particular disease or disease subtype, for example a cancer, e.g., a colon, pancreatic, lung, brain, or breast cancer, which is at least partially driven by a tumor-promoting activity of the TGF-.beta. cellular signaling pathway, and that are therefore likely to respond to inhibitors of the TGF-.beta. cellular signaling pathway or other appropriate treatments for the classified disorder. In particular embodiments, treatment determination can be based on specific TGF-.beta. activity. In a particular embodiment the TGF-.beta. cellular signaling status can be set at a cutoff value of odds of the TGF-.beta. cellular signaling pathway being activate of, for example, 10:1, 5:1, 4:1, 2:1, 1:1, 1:2, 1:4, 1:5, or 1:10.

[0026] In one aspect of the invention, provided herein is a method of determining a TGF-.beta. cellular signaling pathway activity in a subject, for example a human, comprising the steps of: [0027] a. calculating a level of TGF-.beta. transcription factor element in a sample isolated from the subject, wherein the level of the TGF-.beta. transcription factor element in the sample is associated with TGF-.beta. cellular signaling, and wherein the activity level of the TGF-.beta. transcription factor element in the sample are calculated by: [0028] i. receiving data on the expression levels of at least three or more, for example, at least four, at least five, at least six, at least seven or more target genes isolated from the sample, wherein the TGF-.beta. transcription factor element controls transcription of the at least three or more target genes, [0029] ii. calculating the levels of a TGF-.beta. transcription factor element in the sample using a calibrated pathway model, wherein the calibrated pathway model compares the expression levels of the at least three or more target genes in the sample with expression levels of the at least three or more target genes in the calibrated pathway model which defines an activity level of a TGF-.beta. transcription factor element; and, [0030] b. calculating the activity level of the TGF-.beta. cellular signaling pathway in the sample based on the calculated level of TGF-.beta. transcription factor element in the sample.

[0031] In one embodiment, the method further comprises assigning a TGF-.beta. cellular signaling pathway activity status to the calculated activity level of the TGF-.beta. cellular signaling pathway in the sample wherein the activity status is indicative of either an active TGF-.beta. cellular signaling pathway or a passive TGF-.beta. cellular signaling pathway. In one embodiment, the status of the TGF-.beta. cellular signaling pathway is established by establishing a specific threshold for activity as described further below. In one embodiment, the threshold is set as a probability that the cellular signaling pathway is active, for example, a 10:1, 5:1, 4:1, 3:1, 2:1, 1:1, 1:2, 1:4, 1:5, or 1:10. In one embodiment, the activity status is based, for example, on a minimum calculated activity. In one embodiment, the method further comprises assigning to the calculated TGF-.beta. cellular signaling in the sample a probability that the TGF-.beta. cellular signaling pathway is active.

[0032] As contemplated herein, the level of the TGF-.beta. transcription factor element is determined using a calibrated pathway model executed by one or more computer processors, as further described below. The calibrated pathway model compares the expression levels of the at least three target genes in the sample with expression levels of the at least three target genes in the calibrated pathway model which define a level of a TGF-.beta. transcription factor element. In one embodiment, the calibrated pathway model is a probabilistic model incorporating conditional probabilistic relationships that compare the expression levels of the at least three target genes in the sample with expression levels of the at least three target genes in the model which define a level of a TGF-.beta. transcription factor element to determine the level of the TGF-.beta. transcription factor element in the sample. In one embodiment, the probabilistic model is a Bayesian network model. In an alternative embodiment, the calibrated pathway model can be a linear or pseudo-linear model. In an embodiment, the linear or pseudo-linear model is a linear or pseudo-linear combination model.

[0033] As contemplated herein, the expression levels of the unique set of target genes can be determined using standard methods known in the art. For example, the expression levels of the target genes can be determined by measuring the level of mRNA of the target genes, through quantitative reverse transcriptase-polymerase chain reaction techniques, using probes associated with a mRNA sequence of the target genes, using a DNA or RNA microarray, and/or by measuring the protein level of the protein encoded by the target genes. Once the expression level of the target genes is determined, the expression levels of the target genes within the sample can be utilized in the model in a raw state or, alternatively, following normalization of the expression level data. For example, expression level data can be normalized by transforming it into continuous data, z-score data, discrete data, or fuzzy data.

[0034] As contemplated herein, the calculation of TGF-.beta. signaling in the sample is performed on a computerized device having a processor capable of executing a readable program code for calculating the TGF-.beta. signaling in the sample according to the methods described above. Accordingly, the computerized device can include means for receiving expression level data, wherein the data is expression levels of at least three target genes derived from the sample, a means for calculating the level of a TGF-.beta. transcription factor element in the sample using a calibrated pathway model, wherein the calibrated pathway model compares the expression levels of the at least three target genes in the sample with expression levels of the at least three target genes in the model which define a level a TGF-.beta. transcription factor element; a means for calculating the TGF-.beta. cellular signaling in the sample based on the calculated levels of a TGF-.beta. transcription factor element in the sample; and a means for assigning a TGF-.beta. cellular signaling pathway activity probability or status to the calculated TGF-.beta. cellular signaling in the sample, and, optionally, a means for displaying the TGF-.beta. signaling pathway activity probability or status.

[0035] In accordance with another disclosed aspect, further provided herein is a non-transitory storage medium capable of storing instructions that are executable by a digital processing device to perform the method according to the present invention as described herein. The non-transitory storage medium may be a computer-readable storage medium, such as a hard drive or other magnetic storage medium, an optical disk or other optical storage medium, a random access memory (RAM), read only memory (ROM), flash memory, or other electronic storage medium, a network server, or so forth. The digital processing device may be a handheld device (e.g., a personal data assistant or smartphone), a notebook computer, a desktop computer, a tablet computer or device, a remote network server, or so forth.

[0036] Further contemplated herein are methods of treating a subject having a disease or disorder associated with an activated TGF-.beta. cellular signaling pathway, or a disorder whose advancement or progression is exacerbated or caused by, wether partially or wholly, an activated TGF-.beta. cellular signaling pathway, wherein the determination of the TGF-.beta. cellular signaling pathway activity is based on the methods described above, and administering to the subject a TGF-.beta. inhibitor if the information regarding the activity level of TGF-.beta. cellular signaling pathway is indicative of an active TGF-.beta. cellullar signaling pathway. In one embodiment, the disorder is one of an auto-immune and other immune disorders, cancer, bronchial asthma, heart disease, diabetes, hereditary hemorrhagic telangiectasia, Marfan syndrome, Vascular Ehlers-Danlos syndrome, Loeys-Dietz syndrome, Parkinson's disease, Chronic kidney disease, Multiple Sclerosis, fibrotic diseases such as liver, lng, or kidney fibrosis, Dupuytren's disease, or Alzheimer's disease. In a particular embodiment, the subject is suffering from a cancer, for example, a breast cancer, lung cancer, a colon cancer, pancreatic cancer, brain cancer, or breast cancer. In a more particular embodiment, the cancer is a breast cancer.

[0037] Also contemplated herein is a kit for measuring the expression levels of at least three or more TGF-.beta. cellular signaling pathway target genes, for example, four, five, six, seven, eight, nine, ten, eleven, twelve, or more target genes as described herein. In one embodiment, the kit includes one or more components, for example probes, for example labeled probes, and/or PCR primers, for measuring the expression levels of at least three target genes, at least four target genes, at least five target genes, or at least six or more target genes selected from ANGPTL4, CDC42EP3, CDKN1A, CDKN2B, CTGF, GADD45A, GADD45B, HMGA2, ID1, IL11, SERPINE1, INPP5D, JUNB, MMP2, MMP9, NKX2-5, OVOL1, PDGFB, PTHLH, SGK1, SKIL, SMAD4, SMAD5, SMAD6, SMAD7, SNAIL SNAI2, TIMP1, and VEGFA. In one embodiment, the kit includes one or more components for measuring the expression levels of the target genes ANGPTL4 and CDC42EP3, and at least one or more, for example, two, three, four, five, six, seven, or more of CDKN1A, CTGF, GADD45A, GADD45B, HMGA2, ID1, IL11, SERPINE1, JUNB, PDGFB, PTHLH, SGK1, SKIL, SMAD4, SMAD5, SMAD6, SMAD7, SNAI2, and VEGFA. In one embodiment, the kit includes one or more components for measuring the expression levels of the target genes ANGPTL4 and CDC42EP3, and at least one or more, for example, two, three, four, five, six, seven, eight, nine, or ten target genes selected from CDKN1A, CTGF, GADD45B, ID1, IL11, JUNB, PDGFB, SKIL, SMAD7, and SNAI2.

[0038] In one embodiment, the kit includes one or more components for measuring the expression levels of the target genes ANGPTL4 and CDC42EP3, and at least one or more, for example, two, three, four, five, six, seven, eight, nine, or ten of target genes selected from CDKN1A, CTGF, GADD45B, ID1, SERPINE1, JUNB, VEGFA, SKIL, SMAD7, and SNAI2. In one embodiment, the kit includes one or more components for measuring the expression levels of at least the target genes ANGPTL4, CDC42EP3, ID1, SERPINE1, JUNB, SKIL, and SMAD7.

[0039] As contemplated herein, the one or more components or means for measuring the expression levels of the particular target genes can be selected from the group consisting of: an DNA array chip, an oligonucleotide array chip, a protein array chip, an antibody, a plurality of probes, for example, labeled probes, a set of RNA reverser-transcriptase sequencing components, and/or RNA or DNA, including cDNA, amplification primers. In one embodiment, the kit includes a set of labeled probes directed to a portion of an mRNA or cDNA sequence of the targeted genes as described herein. In one embodiment, the kit includes a set of primers and probes directed to a portion of an mRNA or cDNA sequence of the targeted genes as described further below, for example, a set of specific primers or probes selected from the sequences of Table 1 or Table 2. In one embodiment, the labeled probes are contained in a standardized 96-well plate. In one embodiment, the kit further includes primers or probes directed to a set of reference genes, for example, as represented in Table 3. Such reference genes can be, for example, constitutively expressed genes useful in normalizing or standardizing expression levels of the target gene expression levels described herein.

[0040] In one embodiment, the kit further includes a non-transitory storage medium containing instructions that are executable by a digital processing device to perform a method according to the present invention as described herein. In one embodiment, the kit includes an identification code that provides access to a server or computer network for analyzing the activity level of the TGF-.beta. cellular signaling pathway based on the expression levels of the target genes and the methods described herein.

[0041] In one aspect of the invention, provided herein is a method for calculating activity of a TGF-.beta. cellular signaling pathway using mathematical modelling of target gene expressions, namely a method comprising:

[0042] inferring activity of a TGF-.beta. cellular signaling pathway in a subject based at least on expression levels of one or more target gene(s) of the TGF-.beta. cellular signaling pathway measured in a sample of the subject, wherein the calculating comprises:

[0043] inferring a level of a TGF-.beta. transcription factor (TF) element in the sample of the subject, the TGF-.beta. TF element controlling transcription of the one or more target gene(s) of the TGF-.beta. cellular signaling pathway, the determining being based at least in part on evaluating a mathematical model relating expression levels of the one or more target gene(s) of the TGF-.beta. cellular signaling pathway to the level of the TGF-.beta. TF element;

[0044] inferring the activity of the TGF-.beta. cellular signaling pathway in the subject based on the determined level of the TGF-.beta. TF element in the sample of the subject,

[0045] wherein the calculating is performed by a digital processing device using the mathematical model.

BRIEF DESCRIPTION OF THE FIGURES

[0046] FIG. 1 shows schematically and exemplarily TGF-.beta. signaling through the canonical cellular signaling pathway (left part) which is initiated upon binding of the TGF-.beta. protein to the receptor. The initiated cellular signaling pathway ultimately results in the translocation of SMAD2/3 and SMAD4 to the nucleus and binding to the DNA thereby starting target gene transcription (see Sheen Y. Y. et al., "Targeting the transforming growth factor-.beta. signaling in cancer therapy", Biomolecules and Therapeutics, Vol. 21, No. 5, 2013, pages 323 to 331).

[0047] FIG. 2 shows schematically and exemplarily a mathematical model, herein, a Bayesian network model, useful in modelling the transcriptional program of the TGF-.beta. cellular signaling pathway.

[0048] FIG. 3 shows an exemplary flow chart for calculating the activity level of the TGF-.beta. cellular signaling pathway based on expression levels of target genes derived from a sample.

[0049] FIG. 4 shows an exemplary flow chart for obtaining a calibrated pathway model as described herein.

[0050] FIG. 5 shows an exemplary flow chart for calculating the Transcription Factor (TF) Element as described herein.

[0051] FIG. 6 shows an exemplary flow chart for calculating the TGF-.beta. cellular signaling pathway activity level using discretized observables.

[0052] FIG. 7 shows an exemplary flow chart for calculating the TGF-.beta. cellular signaling pathway activity level using continuous observables.

[0053] FIG. 8 shows an exemplary flow chart for determining Cq values from RT-qPCR analysis of the target genes of the TGF-.beta. cellular signaling pathway.

[0054] FIGS. 9 to 12 show training results of the exemplary Bayesian network model based on the evidence curated list of target genes (FIG. 9), the 20 target genes shortlist (FIG. 10), the 12 target genes shortlist (FIG. 11), and the 7 target genes shortlist of the TGF-.beta. cellular signaling pathway (FIG. 12) (see Tables 4 to 7), respectively. (Legend: 1--Control; 2--TGF-.beta. stimulation with 5 ng/mL for 0.5 h; 3--TGF-.beta. stimulation with 5 ng/mL for 1 h; 4--TGF-.beta. stimulation with 5 ng/mL for 2 h; 5--TGF-.beta. stimulation with 5 ng/mL for 4 h; 6--TGF-.beta. stimulation with 5 ng/mL for 8 h; 7--TGF-.beta. stimulation with 5 ng/mL for 16 h; 8--TGF-.beta. stimulation with 5 ng/mL for 24 h; 9--TGF-.beta. stimulation with 5 ng/mL for 72 h)

[0055] FIGS. 13 to 16 show TGF-.beta. cellular signaling pathway activity predictions of the trained exemplary Bayesian network models using the evidence curated list of target genes (FIG. 13), the 20 target genes shortlist (FIG. 14), the 12 target genes shortlist (FIG. 15), and the 7 target genes shortlist (FIG. 16) (see Tables 4 to 7), respectively, for human mammary epithelial cells (HMEC-TR) from GSE28448. (Legend: 1--Control, no TGF-.beta.; 2--Control, TGF-.beta.; 3--siRNA SMAD4, no TGF-.beta.; 4--siRNA SMAD4, TGF-.beta.; 5--siRNA TIF.gamma., no TGF-.beta.; 6--siRNA TIF.gamma., TGF-.beta.)

[0056] FIG. 17 shows TGF-.beta. cellular signaling pathway activity predictions of the trained exemplary Bayesian network model using the evidence curated list of target genes (see Table 4) for ectocervival epithelial cells (Ect1) from GSE35830, which were stimulated with seminal plasma or 5 ng/mL TGF-.beta.. (Legend: 1--Control, no TGF-.beta.; 2--Stimulated with 10% seminal plasma; 3--stimulated with 5 ng/mL TGF-.beta.3)

[0057] FIG. 18 shows TGF-.beta. cellular signaling pathway activity predictions of the trained exemplary Bayesian network model using the evidence curated list of target genes (see Table 4) for patient gliomas from GSE16011. (Legend: 1--Astrocytoma (grade II); 2--Astrocytoma (grade III); 3--Control; 4--Glioblastoma multiforme (grade IV); 5--Oligoastrocytic (grade II); 6--Oligoastrocytic (grade III); 7--Oligodendroglial (grade II); 8--Oligodendroglial (grade III); 9--Pilocytic astrocytoma (grade I))

[0058] FIG. 19 shows TGF-.beta. cellular signaling pathway activity predictions of the trained exemplary Bayesian network model using the evidence curated list of target genes (see Table 4) for breast cancer samples from GSE21653. (Legend: 1--Luminal A; 2--Luminal B; 3--HER2; 4 Basal; 5--Normal-like)

[0059] FIGS. 20 to 23 show TGF-.beta. cellular signaling pathway activity predictions of the trained exemplary Bayesian network models using the evidence curated list of target genes, the 20 target genes shortlist, the 12 target genes shortlist, and the 7 target genes shortlist (see Tables 4 to 7), respectively, for 2D and 3D cultures of A549 lung adenocarcinoma cell lines from GSE42373, which were stimulated with or without a 10 ng/mL TNF and 2 ng/mL TGF-.beta.. (Legend: 1--2D control; 2--2D TGF-.beta. and TNF.alpha.; 3--3D control; 4--3D TGF-.beta. and TNF.alpha.)

[0060] FIG. 24 illustrates a prognosis of glioma patients (GSE16011) depicted in a Kaplan-Meier plot using the trained exemplary Bayesian network model using the evidence curated list of target genes (see Table 4).

[0061] FIG. 25 illustrates a prognosis of breast cancer patients (GSE6532, GSE9195, E-MTAB-365, GSE20685 and GSE21653) depicted in a Kaplan-Meier plot using the trained exemplary Bayesian network model using the evidence curated list of target genes (see Table 4).

[0062] FIG. 26 shows training results of the exemplary Bayesian network model based on the broad literature list of putative target genes of the TGF-.beta. cellular signaling pathway (see Table 8). (Legend: 1--Control; 2--TGF-.beta. stimulation with 5 ng/mL for 0.5 h; 3--TGF-.beta. stimulation with 5 ng/mL for 1 h; 4--TGF-.beta. stimulation with 5 ng/mL for 2 h; 5--TGF-.beta. stimulation with 5 ng/mL for 4 h; 6--TGF-.beta. stimulation with 5 ng/mL for 8 h; 7--TGF-.beta. stimulation with 5 ng/mL for 16 h; 8--TGF-.beta. stimulation with 5 ng/mL for 24 h; 9--TGF-.beta. stimulation with 5 ng/mL for 72 h)

[0063] FIG. 27 shows TGF-.beta. cellular signaling pathway activity predictions of the trained Bayesian network model using the broad literature list of putative target genes (see Table 8) for patient gliomas from GSE16011. (Legend: 1--Astrocytoma (grade II); 2--Astrocytoma (grade III); 3--Control; 4--Glioblastoma multiforme (grade IV); 5--Oligoastrocytic (grade II); 6--Oligoastrocytic (grade III); 7--Oligodendroglial (grade II); 8--Oligodendroglial (grade III); 9--Pilocytic astrocytoma (grade I))

[0064] FIG. 28 shows TGF-.beta. cellular signaling pathway activity predictions of the trained Bayesian network model using the broad literature list of putative target genes (see Table 8) for breast cancer samples from GSE21653. (Legend: 1--Luminal A; 2--Luminal B; 3--HER2; 4--Basal; 5--Normal-like)

[0065] FIG. 29 shows TGF-.beta. pathway activity predictions calculated by the `11-gene list`-Bayesian network on ectocervical epithelial cells (Ect1) stimulated with seminal plasma or 5 ng/mL TGF-.beta.3 (GSE35830). (Legend: 1--Control, no TGF-.beta.; 2--Stimulated with 10% seminal plasma; 3--stimulated with 5 ng/mL TGF-.beta.3)

[0066] FIG. 30 shows TGF-.beta. pathway activity predictions calculated by the `11-gene list+SERPINE1`-Bayesian network on ectocervical epithelial cells (Ect1) stimulated with seminal plasma or 5 ng/mL TGF-.beta.3 (GSE35830). (Legend: 1--Control, no TGF-.beta.; 2--Stimulated with 10% seminal plasma; 3--stimulated with 5 ng/mL TGF-.beta.3)

[0067] FIG. 31 shows TGF-.beta. pathway activity predictions calculated by the `11-gene list`-Bayesian network in 2D and 3D cultures of A549 lung adenocarcinoma cell lines stimulated with or without a 10 ng/mL TNF and 2 ng/mL TGF-.beta. (GSE42373). (Legend: 1--2D control, 2--2D TGF-.beta. and TNF.alpha., 3--3D control, 4--3D TGF-.beta. and TNF.alpha.)

[0068] FIG. 32 shows TGF-.beta. pathway activity predictions calculated by the `11-gene list+SERPINE1`-Bayesian network in 2D and 3D cultures of A549 lung adenocarcinoma cell lines stimulated with or without a 10 ng/mL TNF and 2 ng/mL TGF-.beta. (GSE42373). (Legend: 1--2D control, 2--2D TGF-.beta. and TNF.alpha., 3--3D control, 4--3D TGF-.beta. and TNF.alpha.)

[0069] FIG. 33 shows TGF-.beta. pathway activity predictions calculated by the `11-gene list`-Bayesian on glioma patients and some control samples from GSE16011. (Legend: 1--Astrocytoma (grade II); 2--Astrocytoma (grade III); 3--Control; 4--Glioblastoma multiforme (grade IV); 5--Oligoastrocytic (grade II); 6--Oligoastrocytic (grade III); 7--Oligodendroglial (grade II); 8--Oligodendroglial (grade III); 9--Pilocytic astrocytoma (grade I))

[0070] FIG. 34 shows TGF-.beta. pathway activity predictions calculated by the `11-gene list+SERPINE1`-Bayesian on glioma patients and some control samples from GSE16011. (Legend: 1--Astrocytoma (grade II); 2--Astrocytoma (grade III); 3--Control; 4--Glioblastoma multiforme (grade IV); 5--Oligoastrocytic (grade II); 6--Oligoastrocytic (grade III); 7--Oligodendroglial (grade II); 8--Oligodendroglial (grade III); 9--Pilocytic astrocytoma (grade I))

DETAILED DESCRIPTION OF THE INVENTION

[0071] Provided herein are methods and apparatuses, and in particular computer implemented methods and apparatuses, for determining the activity levels of a TGF-.beta. cellular signaling pathway in a subject, wherein the TGF-.beta. cellular signaling is calculated by a) calculating an activity level of TGF-.beta. transcription factor element in a sample isolated from a subject, and wherein the activity levels of the TGF-.beta. transcription factor element in the sample is calculated by measuring the expression levels of a unique set of target genes, wherein the TGF-.beta. transcription factor element controls transcription of the target genes, calculating the levels of the TGF-.beta. transcription factor element in the sample using a calibrated pathway model, wherein the calibrated pathway model compares the expression levels of the target genes in the sample with expression levels of the target genes in the calibrated pathway model which define a level of a TGF-.beta. transcription factor element; and calculating the TGF-.beta. cellular signaling in the sample based on the calculated levels of TGF-.beta. transcription factor element in the sample.

[0072] In particular, the unique set of target genes whose expression levels is analyzed in the model includes at least three or more genes, for example, three, four, five, six, or seven target genes selected from ANGPTL4, CDC42EP3, ID1, IL11, SERPINE1, JUNB, SKIL, or SMAD7. It has been discovered that analyzing a specific set of target genes as described herein in the disclosed pathway model provides for an advantageously accurate TGF-.beta. cellular signaling pathway activity determination. Accordingly, such status can be used to, for example but not limited to, identify the presence or absence of disease and/or particular disease state or advancement, diagnose a specific disease or disease state, or diagnose the presence or absence of a particular disease, derive a course of treatment based on the presence or absence of TGF-.beta. signaling activity, monitor disease progression in order to, for example, adjust therapeutic protocols based on a predicted drug efficacy in light of the determined activity of the TGF-.beta. signaling pathway in the sample, or develop TGF-.beta. targeted therapeutics.

DEFINITIONS

[0073] All terms used herein are intended to have their plain and ordinary meaning as normally ascribed in the art unless otherwise specifically indicated herein.

[0074] Herein, the "level" of a TF element denotes the level of activity of the TF element regarding transcription of its target genes.

[0075] The term "subject" or "host", as used herein, refers to any living being. In some embodiments, the subject is an animal, for example a mammal, including a human. In a particular embodiment, the subject is a human. In one embodiment, the human is suspected of having a disorder mediated or exacerbated by an active TGF-.beta. cellular signaling pathway, for example, a cancer. In one embodiment, the human has or is suspected of having a breast cancer.

[0076] The term "sample", as used herein, means any biological specimen isolated from a subject. Accordingly, "sample" as used herein is contemplated to encompasses the case where e.g. a tissue and/or cells and/or a body fluid of the subject have been isolated from the subject. Performing the claimed method may include where a portion of this sample is extracted, e.g., by means of Laser Capture Microdissection (LCM), or by scraping off the cells of interest from the slide, or by fluorescence-activated cell sorting techniques. In addition, the term "sample", as used herein, also encompasses the case where e.g. a tissue and/or cells and/or a body fluid of the subject has been taken from the subject and has been put on a microscope slide, and the claimed method is performed on the slide. In addition, the term "samples," as used herein, may also encompass circulating tumor cells or CTCs.

[0077] The term "TGF-.beta. transcription factor element" or "TGF-.beta. TF element" or "TF element" refers to a signaling agent downstream of the binding of TGF-.beta. to its receptor which controls target gene expression, which may be a transcription factor protein or protein complex or a precursor of an active transcription protein complex. It can be, in embodiments, a signaling agent triggered by the binding of TGF-.beta. to its receptor downstream of TGF-.beta. extracellular receptor binding and upstream of the formation of the active transcription factor protein complex. For example, it is known that when TGF-.beta. binds to an extracellular TGF-.beta. receptor, it initiates an intracellular "SMAD" signaling pathway and that one or more SMAD proteins (for example receptor-regulated or R-SMADs (SMAD 1, 2, 3, 5 and 8) and SMAD4) participate in, and may form a heterocomplex which participates in, the TGF-.beta. transcription signaling cascade which controls expression.

[0078] The term "target gene" as used herein, means a gene whose transcription is directly or indirectly controlled by a TGF-.beta. transcription factor element. The "target gene" may be a "direct target gene" and/or an "indirect target gene" (as described herein).

[0079] As contemplated herein, target genes include at least ANGPTL4, CDC42EP3, CDKN1A, CDKN2B, CTGF, GADD45A, GADD45B, HMGA2, ID1, IL11, SERPINE1, INPP5D, JUNB, MMP2, MMP9, NKX2-5, OVOL1, PDGFB, PTHLH, SGK1, SKIL, SMAD4, SMAD5, SMAD6, SMAD7, SNAI1, SNAI2, TIMP1, and VEGFA.

[0080] As contemplated herein, the present invention includes: [0081] A) A computer implemented method for determining the activity level of a TGF-.beta. cellular signaling pathway in a subject performed by a computerized device having a processor comprising: [0082] a. calculating an activity level a TGF-.beta. transcription factor element in a sample isolated from the subject, wherein the activity level of the TGF-.beta. transcription factor element in the sample is calculated by: [0083] i. receiving data on the expression levels of at least three target genes derived from the sample, wherein the TGF-.beta. transcription factor element controls transcription of the at least three target genes, and wherein the at least three target genes are selected from CDC42EP3, ANGPTL4, ID1, IL11, SERPINE1, JUNB, SKIL, and SMAD7; [0084] ii. calculating the activity level of the TGF-.beta. transcription factor element in the sample using a calibrated pathway model, wherein the calibrated pathway model compares the expression levels of the at least three target genes in the sample with expression levels of the at least three target genes in the model which define an activity level of the TGF-.beta. transcription factor element; and, [0085] b. calculating the activity level of the TGF-.beta. cellular signaling pathway in the sample based on the calculated activity levels of TGF-.beta. transcription factor element in the sample.

[0086] In one embodiment, the method further comprises assigning a TGF-.beta. cellular signaling pathway activity status to the calculated activity level of the TGF-.beta. cellular signaling in the sample, wherein the activity status is indicative of either an active TGF-.beta. cellular signaling pathway or a passive TGF-.beta. cellular signaling pathway. In one embodiment, the method further comprises displaying the TGF-.beta. cellular signaling pathway activity status. In one embodiment, the at least three target genes are ANGPTL4, and at least two of CDC42EP3, ID1, IL11, SERPINE1, JUNB, SKIL, or SMAD7. In one embodiment, the at least three target genes are ANGPTL4, CDC42EP3, and at least one of ID1, IL11, SERPINE1, JUNB, SKIL, or SMAD7. In one embodiment, data on the expression levels of the target genes ANGPTL4, CDC42EP3, ID1, IL11, JUNB, SKIL, and SMAD7 is received. In one embodiment, data on the expression levels of the target genes ANGPTL4, CDC42EP3, ID1, SERPINE1, JUNB, SKIL, and SMAD7 is received. In one embodiment, data on at least one additional target gene selected from CDKN1A, CTGF, GADD45B, PDGFB, VEGFA, and SNAI2 is received. In one embodiment, data on the expression levels of the additional target genes CDKN1A, CTGF, GADD45B, PDGFB, and SNAI2 is received. In one embodiment, data on the expression levels of the additional target genes CDKN1A, CTGF, GADD45B, VEGFA, and SNAI2 is received. In one embodiment, data on at least one additional target gene selected from CDKN1A, CTGF, GADD45B, PDGFB, VEGFA, and SNAI2 is received. In one embodiment, data on the expression levels of the additional target genes CDKN1A, CTGF, GADD45B, PDGFB, and SNAI2 is received. In one embodiment, data on the expression levels of the additional target genes CDKN1A, CTGF, GADD45B, VEGFA, and SNAI2 is received. In one embodiment, data on the expression levels of the additional target genes CDKN2B, GADD45A, HMGA2, INPP5D, MMP2, MMP9, NKX2-5, OVOL1, PTHLH, SGK1, SMAD4, SMAD5, SMAD6, SNAI1, and TIMP1 is received. In one embodiment, data on the expression levels of the additional target genes CDKN2B, GADD45A, HMGA2, INPP5D, MMP2, MMP9, NKX2-5, OVOL1, PTHLH, SGK1, SMAD4, SMAD5, SMAD6, SNAIL and TIMP1 is received. In one embodiment, data on the expression levels of the additional target genes CDKN2B, GADD45A, HMGA2, INPP5D, MMP2, MMP9, NKX2-5, OVOL1, PTHLH, SGK1, SMAD4, SMAD5, SMAD6, SNAI1, and TIMP1 is received. In one embodiment, data on the expression levels of the additional target genes CDKN2B, GADD45A, HMGA2, INPP5D, MMP2, MMP9, NKX2-5, OVOL1, PTHLH, SGK1, SMAD4, SMAD5, SMAD6, SNAIL and TIMP1 is received. In one embodiment, the calibrated pathway model is a probabilistic model incorporating conditional probabilistic relationships that compare the expression levels of the at least three target genes in the sample with expression levels of the at least three target genes in the model which define a level of TGF-.beta. transcription factor element to determine the activity level of the TGF-.beta. transcription factor element in the sample. In one embodiment, the probabilistic model is a Bayesian network model. In one embodiment, the calibrated pathway model is a linear model incorporating relationships that compare the expression levels of the at least three target genes in the sample with expression levels of the at least three target genes in the model which define a level of TGF-.beta. transcription factor element to determine the activity level of the TGF-.beta. transcription factor element in the sample. [0087] B) A computer program product for determining the activity level of a TGF-.beta. cellular signaling pathway in a subject comprising [0088] a. a non-transitory computer readable storage medium having computer readable program code embodied therewith, the computer readable program code executable by at least one processor to: [0089] i. calculate a level of TGF-.beta. transcription factor element in a sample isolated from a subject, wherein the level of the TGF-.beta. transcription factor element in the sample is calculated by: [0090] 1. receiving data on the expression levels of at least three target genes derived from the sample, wherein the at least three target genes are selected from CDC42EP3, ANGPTL4, ID1, IL11, SERPINE1, JUNB, SKIL, and SMAD7; [0091] 2. calculating the level of the TGF-.beta. transcription factor element in the sample using a calibrated pathway model, wherein the calibrated pathway model compares the expression levels of the at least three target genes in the sample with expression levels of the at least three target genes in the model which define an activity level of TGF-.beta. transcription factor element; and, [0092] ii. calculate the activity level of the TGF-.beta. cellular signaling pathway in the sample based on the calculated TGF-.beta. transcription factor element level in the sample.

[0093] In one embodiment, the computer readable program code is executable by at least one processor to assign a TGF-.beta. cellular signaling pathway activity status to the calculated activity level of the TGF-.beta. cellular signaling in the sample, wherein the activity status is indicative of either an active TGF-.beta. cellular signaling pathway or a passive TGF-.beta. cellular signaling pathway. In one embodiment, the computer readable program code is executable by at least one processor to display the TGF-.beta. signaling pathway activity status. In one embodiment, the at least three target genes are ANGPTL4, and at least two of CDC42EP3, ID1, IL11, SERPINE1, JUNB, SKIL, or SMAD7. In one embodiment, the at least three target genes are ANGPTL4, CDC42EP3, and at least one of ID1, IL11, SERPINE1, JUNB, SKIL, or SMAD7. In one embodiment, the data on the expression levels of the target genes ANGPTL4, CDC42EP3, ID1, IL11, JUNB, SKIL, and SMAD7 is received. In one embodiment, the data on the expression levels of the target genes ANGPTL4, CDC42EP3, ID1, SERPINE1, JUNB, SKIL, and SMAD7 is received. In one embodiment, data on at least one additional target gene selected from CDKN1A, CTGF, GADD45B, PDGFB, VEGFA, and SNAI2 is received. In one embodiment, data on the expression levels of the additional target genes CDKN1A, CTGF, GADD45B, PDGFB, and SNAI2 is received. In one embodiment, data on the expression levels of the additional target genes CDKN1A, CTGF, GADD45B, VEGFA, and SNAI2 is received. In one embodiment, data on at least one additional target gene selected from CDKN1A, CTGF, GADD45B, PDGFB, VEGFA, and SNAI2 is received. In one embodiment, data on the expression levels of the additional target genes CDKN1A, CTGF, GADD45B, PDGFB, and SNAI2 is received. In one embodiment, data on the expression levels of the additional target genes CDKN1A, CTGF, GADD45B, VEGFA, and SNAI2 is received. In one embodiment, data on the expression levels of at least one additional target gene selected from CDKN2B, GADD45A, HMGA2, INPP5D, MMP2, MMP9, NKX2-5, OVOL1, PTHLH, SGK1, SMAD4, SMAD5, SMAD6, SNAI1, and TIMP1 is received. In one embodiment, data on the expression levels of at least one additional target gene selected from CDKN2B, GADD45A, HMGA2, INPP5D, MMP2, MMP9, NKX2-5, OVOL1, PTHLH, SGK1, SMAD4, SMAD5, SMAD6, SNAI1, and TIMP1 is received. In one embodiment, data on the expression levels of at least one additional target gene selected from CDKN2B, GADD45A, HMGA2, INPP5D, MMP2, MMP9, NKX2-5, OVOL1, PTHLH, SGK1, SMAD4, SMAD5, SMAD6, SNAIL and TIMP1 is received. In one embodiment, data on the expression levels of at least one additional target gene selected from CDKN2B, GADD45A, HMGA2, INPP5D, MMP2, MMP9, NKX2-5, OVOL1, PTHLH, SGK1, SMAD4, SMAD5, SMAD6, SNAIL and TIMP1 is received. In one embodiment, the calibrated pathway model is a probabilistic model incorporating conditional probabilistic relationships that compare the expression levels of the at least three target genes in the sample with expression levels of the at least three target genes in the model which define a level of TGF-.beta. transcription factor element to determine the activity level of TGF-.beta. transcription factor element in the sample. In one embodiment, the probabilistic model is a Bayesian network model. In one embodiment, the calibrated pathway model is a linear model incorporating relationships that compare the expression levels of the at least three target genes in the sample with expression levels of the at least three target genes in the model which define a level of TGF-.beta. transcription factor element to determine the activity level of aTGF-.beta. transcription factor element in the sample. [0094] C) A method of treating a subject suffering from a disease associated with an activated TGF-.beta. cellular signaling pathway comprising: [0095] a. receiving information regarding the activity level of a TGF-.beta. cellular signaling pathway derived from a sample isolated from the subject, wherein the activity level of the TGF-.beta. cellular signaling pathway is determined by: [0096] i. calculating an activity level of TGF-.beta. transcription factor element in a sample isolated from the subject, wherein the level of the TGF-.beta. transcription factor element in the sample is calculated by: [0097] 1. receiving data on the expression levels of at least three target genes derived from the sample, wherein the TGF-.beta. transcription factor element controls transcription of the at least three target genes, and wherein the at least three target genes are selected from CDC42EP3, ANGPTL4, ID1, IL11, SERPINE1, JUNB, SKIL, and SMAD7; [0098] 2. calculating the level of the TGF-.beta. transcription factor element in the sample using a calibrated pathway model, wherein the calibrated pathway model compares the expression levels of the at least three target genes in the sample with expression levels of the at least three target genes in the model which define an activity level of the TGF-.beta. transcription factor element; and, [0099] ii. calculating the activity level of the TGF-.beta. cellular signaling pathway in the sample based on the calculated TGF-.beta. transcription factor element level in the sample; and, [0100] b. administering to the subject a TGF-.beta. inhibitor if the information regarding the activity level of the TGF-.beta. cellular signaling pathway is indicative of an pathogenically active TGF-.beta. cellular signaling pathway.

[0101] In one embodiment, the at least three target genes are ANGPTL4, and at least two of CDC42EP3, ID1, IL11, SERPINE1, JUNB, SKIL, or SMAD7. In one embodiment, the at least three target genes are ANGPTL4, CDC42EP3, and at least one of ID1, IL11, SERPINE1, JUNB, SKIL, or SMAD7. In one embodiment, data on the expression levels of the target genes ANGPTL4, CDC42EP3, ID1, IL11, JUNB, SKIL, and SMAD7 is received. In one embodiment, data on the expression levels of the target genes ANGPTL4, CDC42EP3, ID1, SERPINE1, JUNB, SKIL, and SMAD7 is received. In one embodiment, data on at least one additional target gene selected from CDKN1A, CTGF, GADD45B, PDGFB, VEGFA, and SNAI2 is received. In one embodiment, data on the expression levels of the additional target genes CDKN1A, CTGF, GADD45B, PDGFB, and SNAI2 is received. In one embodiment, data on the expression levels of the additional target genes CDKN1A, CTGF, GADD45B, VEGFA, and SNAI2 is received. In one embodiment, data on at least one additional target gene selected from CDKN1A, CTGF, GADD45B, PDGFB, VEGFA, and SNAI2 is received. In one embodiment, data on the expression levels of the additional target genes CDKN1A, CTGF, GADD45B, PDGFB, and SNAI2 is received. In one embodiment, data on the expression levels of the additional target genes CDKN1A, CTGF, GADD45B, VEGFA, and SNAI2 is received. In one embodiment, data on the expression levels of the additional target genes CDKN2B, GADD45A, HMGA2, INPP5D, MMP2, MMP9, NKX2-5, OVOL1, PTHLH, SGK1, SMAD4, SMAD5, SMAD6, SNAI1, and TIMP1 is received. In one embodiment, data on the expression levels of the additional target genes CDKN2B, GADD45A, HMGA2, INPP5D, MMP2, MMP9, NKX2-5, OVOL1, PTHLH, SGK1, SMAD4, SMAD5, SMAD6, SNAIL and TIMP1 is received. In one embodiment, data on the expression levels of the additional target genes CDKN2B, GADD45A, HMGA2, INPP5D, MMP2, MMP9, NKX2-5, OVOL1, PTHLH, SGK1, SMAD4, SMAD5, SMAD6, SNAI1, and TIMP1 is received. In one embodiment, data on the expression levels of the additional target genes CDKN2B, GADD45A, HMGA2, INPP5D, MMP2, MMP9, NKX2-5, OVOL1, PTHLH, SGK1, SMAD4, SMAD5, SMAD6, SNAIL and TIMP1 is received. In one embodiment, the calibrated pathway model is a probabilistic model incorporating conditional probabilistic relationships that compare the expression levels of the at least three target genes in the sample with expression levels of the at least three target genes in the model which define a level of TGF-.beta. transcription factor element to determine the activity level of the TGF-.beta. transcription factor element in the sample. In one embodiment, the probabilistic model is a Bayesian network model. In one embodiment, the calibrated pathway model is a linear model incorporating relationships that compare the expression levels of the at least three target genes in the sample with expression levels of the at least three target genes in the model which define a level of TGF-.beta. transcription factor element to determine the activity level of the TGF-.beta. transcription factor element in the human cancer sample. In illustrative embodiment, the TGF-.beta. inhibitor is Terameprocol, Fresolimumab, Sotatercept, Galunisertib, SB431542, LY2109761, LDN-193189, SB525334, SB505124, GW788388, LY364947, RepSox, LDN-193189 HCl, K02288, LDN-214117, SD-208, EW-7197, ML347, LDN-212854, DMH1, Pirfenidone, Hesperetin, Trabedersen, Lerdelimumab, Metelimumab, trx-SARA, ID11, Ki26894, or SB-431542. In one embodiment, the disease is a cancer. In one embodiment, the cancer is colon, breast, prostate, pancreatic, lung, brain, leukemia, lymphoma, or glioma. In one embodiment, the cancer is breast cancer. [0102] D) A kit for measuring expression levels of TGF-.beta. cellular signaling pathway target genes comprising: [0103] a. a set of polymerase chain reaction primers directed to at least six TGF-.beta. cellular signaling pathway target genes from a sample isolated from a subject; and [0104] b. a set of probes directed to the at least six TGF-.beta. cellular signaling pathway target genes; [0105] wherein the at least six TGF-.beta. cellular signaling pathway target genes are selected from CDC42EP3, ANGPTL4, ID1, SERPINE1, JUNB, SKIL, and SMAD7.

[0106] In one embodiment, the at least six target genes are ANGPTL4, and at least five of CDC42EP3, ID1, IL11, SERPINE1, JUNB, SKIL, or SMAD7. In one embodiment, the at least six target genes are ANGPTL4, CDC42EP3, and at least four of ID1, IL11, SERPINE1, JUNB, SKIL, or SMAD7. In one embodiment, the target genes are ANGPTL4, CDC42EP3, ID1, IL11, JUNB, SKIL, and SMAD7. In one embodiment, the target genes are ANGPTL4, CDC42EP3, ID1, SERPINE1, JUNB, SKIL, and SMAD7. In one embodiment, the kit includes at least one additional set of primers and probes directed to a target gene selected from CDKN1A, CTGF, GADD45B, PDGFB, VEGFA, and SNAI2. In one embodiment, the kit includes additional sets of primers and probes directed to target genes CDKN1A, CTGF, GADD45B, PDGFB, and SNAI2. In one embodiment, the kit includes additional sets of primers and probes directed to target genes CDKN1A, CTGF, GADD45B, VEGFA, and SNAI2. In one embodiment, the kit includes at least one additional set of primers and probes directed to a target gene selected from CDKN1A, CTGF, GADD45B, PDGFB, VEGFA, and SNAI2. In one embodiment, the kit includes additional sets of primers and probes directed to target genes CDKN1A, CTGF, GADD45B, PDGFB, and SNAI2. In one embodiment, the kit includes additional sets of primers and probes directed to target genes CDKN1A, CTGF, GADD45B, VEGFA, and SNAI2. In one embodiment, the kit includes additional sets of primers and probes directed to target genes CDKN2B, GADD45A, HMGA2, INPP5D, MMP2, MMP9, NKX2-5, OVOL1, PTHLH, SGK1, SMAD4, SMAD5, SMAD6, SNAIL and TIMP1. In one embodiment, the kit includes additional sets of primers and probes directed to target genes CDKN2B, GADD45A, HMGA2, INPP5D, MMP2, MMP9, NKX2-5, OVOL1, PTHLH, SGK1, SMAD4, SMAD5, SMAD6, SNAIL and TIMP1. In one embodiment, the kit includes additional sets of primers and probes directed to target genes CDKN2B, GADD45A, HMGA2, INPP5D, MMP2, MMP9, NKX2-5, OVOL1, PTHLH, SGK1, SMAD4, SMAD5, SMAD6, SNAIL and TIMP1. In one embodiment, the kit includes additional sets of primers and probes directed to target genes CDKN2B, GADD45A, HMGA2, INPP5D, MMP2, MMP9, NKX2-5, OVOL1, PTHLH, SGK1, SMAD4, SMAD5, SMAD6, SNAIL and TIMP1. In one embodiment, the probes are labeled. In one embodiment, the set of probes are SEQ. ID. NOS.74, 77, 80, 83, 86, 89, 92, 95, 98, 101, 104, and 107. In one embodiment, the set of primers are SEQ. ID. NOS. 72 and 73, 75 and 76, 78 and 79, 81 and 82, 84 and 85, 87 and 88, 90 and 91, 93 and 94, 96 and 97, 99 and 100, 102 and 103, and 105 and 106. In one embodiment, a computer program product for determining the activity level of a TGF-.beta. cellular signaling pathway in the subject comprising a non-transitory computer readable storage medium having computer readable program code embodied therewith, the computer readable program code executable by at least one processor to: (i) calculate a level of TGF-.beta. transcription factor element in the sample, wherein the level of the TGF-.beta. transcription factor element in the sample is associated with TGF-.beta. cellular signaling, and wherein the level of the TGF-.beta. transcription factor element in the sample is calculated by: (1) receiving data on the expression levels of the at least six target genes derived from the sample; (2) calculating the level of the TGF-.beta. transcription factor element in the sample using a calibrated pathway model, wherein the calibrated pathway model compares the expression levels of the at least six target genes in the sample with expression levels of the at least six target genes in the model which define an activity level of TGF-.beta. transcription factor element; and, (ii) calculate the activity level of the TGF-.beta. cellular signaling pathway in the sample based on the calculated TGF-.beta. transcription factor element level in the sample. [0107] E) A kit for determining the activity level of a TGF-.beta. cellular signaling pathway in a subject comprising: [0108] a. one or more components capable of identifying expression levels of at least three TGF-.beta. cellular signaling pathway target genes from a sample of the subject, wherein the at least three TGF-.beta. cellular signaling pathway target genes are selected from CDC42EP3, ANGPTL4, ID1, SERPINE1, JUNB, SKIL, or SMAD7; and, [0109] b. a non-transitory computer readable storage medium having computer readable program code embodied therewith, the computer readable program code executable by at least one processor to: [0110] i. calculate a level of TGF-.beta. transcription factor element in the sample, wherein the level of TGF-.beta. transcription factor element in the sample is associated with TGF-.beta. cellular signaling, and wherein the level of the TGF-.beta. transcription factor element in the sample is calculated by: [0111] 1. receiving data on the expression levels of the at least three target genes derived from the sample; [0112] 2. calculating the level of the TGF-.beta. transcription factor element in the sample using a calibrated pathway model, wherein the calibrated pathway model compares the expression levels of the at least three target genes in the sample with expression levels of the at least three target genes in the model which define an activity level of the TGF-.beta. transcription factor element; and, [0113] ii. calculate the activity level of the TGF-.beta. cellular signaling pathway in the sample based on the calculated TGF-.beta. transcription factor element level in the sample.

Determining the Activity Level of the TGF-.beta. Cellular Signaling Pathway

[0114] The present invention provides new and improved methods and apparatuses, and in particular computer implemented methods and apparatuses, as disclosed herein, to assess the functional state or activity of the TGF-.beta. cellular signaling pathway.

[0115] In one aspect of the invention, provided herein is a method of determining TGF-.beta. cellular signaling in a subject comprising the steps of: [0116] a. calculating a level of TGF-.beta. transcription factor element in a sample isolated from a subject, wherein the level of TGF-.beta. transcription factor element in the sample is associated with an activity level of the TGF-.beta. cellular signaling pathway, and wherein the activity level of the TGF-.beta. transcription factor element in the sample is calculated by: [0117] i. receiving data on the expression levels of at least three or more target genes derived from the sample, wherein the TGF-.beta. transcription factor element controls transcription of the at least three or more target genes, [0118] ii. calculating the level of TGF-.beta. transcription factor element in the sample using a calibrated pathway model, wherein the calibrated pathway model compares the expression levels of the at least three or more target genes in the sample with expression levels of the at least three or more target genes in the calibrated pathway model which define an activity level of the TGF-.beta. transcription factor element; and, [0119] b. calculating the activity level of the TGF-.beta. cellular signaling pathway in the sample based on the calculated levels of TGF-.beta. transcription factor element in the sample. As contemplated herein, the method of calculating the activity level of the TGF-.beta. cellular signaling pathway is performed by a computer processor.

[0120] As a non-limiting generalized example, FIG. 2 provides an exemplary flow diagram used to determine the activity level of the TGF-.beta. cellular signaling pathway based on a computer implemented mathematical model constructed of three nodes: (a) a transcription factor (TF) element (for example, but not limited to being, discretized into the states "absent" and "present" or as a continuous observable) in a first layer 1; (b) target gene(s) TG.sub.1, TG.sub.2, TG.sub.n (for example, but not limited to being, discretized into the states "down" and "up" or as a continuous observable) in a second layer 2, and; (c) measurement nodes linked to the expression levels of the target gene(s) in a third layer 3. The expression levels of the target genes can be determined by, for example, but not limited to, microarray probesets PS.sub.1,1, PS.sub.1,2, PS.sub.1,3, PS.sub.2,1, PS.sub.n,1, PS.sub.n,m (for example, but limited to being, discretized into the states "low" and "high" or as a continuous observable), but could also be any other gene expression measurements such as, for example, RNAseq or RT-qPCR. The expression of the target genes depends on the activation of the respective transcription factor element, and the measured intensities of the selected probesets depend in turn on the expression of the respective target genes. The model is used to calculate TGF-B pathway activity by first determining probeset intensities, i.e., the expression level of the target genes, and calculating backwards in the model what the probability is that the transcription factor element must be present.

[0121] The present invention makes it possible to determine the activity of the TGF-.beta. cellular signaling pathway in a subject by (i) determining a level of a TGF-.beta. TF element in the sample of the subject, wherein the determining is based at least in part on evaluating a mathematical model relating expression levels of one or more target gene(s) of the TGF-.beta. cellular signaling pathway, the transcription of which is controlled by the TGF-.beta. TF element, to the level of the TGF-.beta. TF element, and by (ii) calculating the activity of the TGF-.beta. cellular signaling pathway in the subject based on the determined level of the TGF-.beta. TF element in the sample of the subject. This, for example, allows improving the possibilities of characterizing patients that have a disease, for example, cancer, e.g., a colon, pancreatic, lung, brain or breast cancer, which is at least partially driven by a tumor-promoting activity of the TGF-.beta. cellular signaling pathway, and that are therefore likely to respond to inhibitors of the TGF-.beta. cellular signaling pathway.

Generalized Workflow for Determining the Activity Level of TGF-.beta. Cellular Signaling

[0122] An example flow chart illustrating an exemplary calculation of the activity level of TGF-.beta. cellular signaling from a sample isolated from a subject is provided in FIG. 3. First, the mRNA from a sample is isolated (11). Second, the mRNA expression levels of a unique set of at least three or more TGF-.beta. target genes, as described herein, are measured (12) using methods for measuring gene expression that are known in the art. Next, the calculation of transcription factor element (13) is calculated using a calibrated pathway model (14), wherein the calibrated pathway model compares the expression levels of the at least three or more target genes in the sample with expression levels of the at least three target genes in the calibrated pathway model which have been correlated with a level of a TGF-.beta. transcription factor element. Finally, the activity level of the TGF-.beta. cellular signaling pathway is calculated in the sample based on the calculated levels of TGF-.beta. transcription factor element in the sample (15). For example, the TGF-.beta. signaling pathway is determined to be active if the activity is above a certain threshold, and can be categorized as passive if the activity falls below a certain threshold.

Target Genes

[0123] The present invention utilizes the analyses of the expression levels of unique sets of target genes. Particularly suitable target genes are described in the following text passages as well as the examples below (see, e.g., Tables 4-7, 9, and 11-12 below).

[0124] Thus, according to an embodiment the target gene(s) is/are selected from the group consisting of the target genes listed in Table 4, Table 5, Table 6, Table 7, Table 9, Table 11, or Table 12, below.

[0125] In particular, the unique set of target genes whose expression is analyzed in the model includes at least three or more target genes, for example, three, four, five, six, seven or more, selected from ANGPTL4, CDC42EP3, ID1, IL11, SERPINE1, JUNB, SKIL, or SMAD7.

[0126] In one embodiment, the at least three target genes are ANGPTL4, and at least two of CDC42EP3, ID1, IL11, JUNB, SKIL, or SMAD7. In one embodiment, the at least three target genes are CDC42EP3, and at least two of ANGPTL4, ID1, IL11, JUNB, SKIL, or SMAD7.

[0127] In one embodiment, the at least three target genes are ANGPTL4, and at least two of CDC42EP3, ID1, SERPINE1, JUNB, SKIL, or SMAD7. In one embodiment, the at least three target genes are CDC42EP3, and at least two of ANGPTL4, ID1, SERPINE1, JUNB, SKIL, or SMAD7.

[0128] In one embodiment, the at least three target genes are ANGPTL4, CDC42EP3, and at least one of ID1, IL11, JUNB, SKIL, or SMAD7. In one embodiment, the at least three target genes are ANGPTL4, CDC42EP3, and at least one of ID1, SERPINE1, JUNB, SKIL, or SMAD7.

[0129] In one embodiment, the expression levels of the target genes ANGPTL4, CDC42EP3, ID1, IL11, JUNB, SKIL, and SMAD7 are used in calculating the activity level of the TGF-.beta. cellular signaling pathway.

[0130] In one embodiment, the expression levels of the target genes ANGPTL4, CDC42EP3, ID1, SERPINE1, JUNB, SKIL, and SMAD7 is used in calculating TGF-.beta. cellular signaling.

[0131] In one embodiment, the expression level of at least one additional target gene selected from CDKN1A, CTGF, GADD45B, PDGFB, and SNAI2 is used in calculating TGF-.beta. cellular signaling. In one embodiment, the expression levels of the additional target genes CDKN1A, CTGF, GADD45B, PDGFB, and SNAI2 are used in calculating TGF-.beta. cellular signaling. In one embodiment, the expression levels of target genes ANGPTL4, CDC42EP3, ID1, IL11, JUNB, SKIL, SMAD7, CDKN1A, CTGF, GADD45B, PDGFB, and SNAI2 are used in calculating TGF-.beta. cellular signaling.

[0132] In one embodiment, the expression level of at least one additional target gene selected from CDKN1A, CTGF, GADD45B, VEGFA, and SNAI2 is used in calculating TGF-.beta. cellular signaling. In one embodiment, the expression levels of the additional target genes CDKN1A, CTGF, GADD45B, VEGFA, and SNAI2 are used in calculating TGF-.beta. cellular signaling. In one embodiment, the expression levels of target genes ANGPTL4, CDC42EP3, ID1, IL11, JUNB, SKIL, SMAD7, CDKN1A, CTGF, GADD45B, VEGFA, and SNAI2 are used in calculating TGF-.beta. cellular signaling. In one embodiment, the expression levels of target genes ANGPTL4, CDC42EP3, ID1, SERPINE1, JUNB, SKIL, SMAD7, CDKN1A, CTGF, GADD45B, VEGFA, and SNAI2 are used in calculating TGF-.beta. cellular signaling.

[0133] As contemplated herein, the expression levels of other target genes, in further addition to those described above, may be included in the pathway modeling to calculate activity levels of pathway the TGF-.beta. cellular signaling pathway, including GADD45A, HMGA2, PTHLH, SGK1, SMAD4, SMAD5, SMAD6, SMAD7, VEGFA, INPP5D, MMP2, MMP9, NKX2-5, OVOL1, and TIMP1.

[0134] In one embodiment, the method comprises:

[0135] calculating the activity of the TGF-.beta. cellular signaling pathway in the subject based at least on expression levels of one or more, two or more, or at least three, target gene(s) of the TGF-.beta. cellular signaling pathway measured in the sample of the subject selected from the group consisting of: ANGPTL4, CDC42EP3, CDKN1A, CDKN2B, CTGF, GADD45A, GADD45B, HMGA2, ID1, IL11, INPP5D, JUNB, MMP2, MMP9, NKX2-5, OVOL1, PDGFB, PTHLH, SGK1, SKIL, SMAD4, SMAD5, SMAD6, SMAD7, SNAI1, SNAI2, TIMP1, and VEGFA, or from the group consisting of: ANGPTL4, CDC42EP3, CDKN1A, CTGF, GADD45A, GADD45B, HMGA2, ID1, IL11, JUNB, PDGFB, PTHLH, SGK1, SKIL, SMAD4, SMAD5, SMAD6, SMAD7, SNAI2, and VEGFA, or from the group consisting of: ANGPTL4, CDC42EP3, CDKN1A, CTGF, GADD45B, ID1, IL11, JUNB, PDGFB, SKIL, SMAD7, and SNAI2, or from the group consisting of: ANGPTL4, CDC42EP3, ID1, IL11, JUNB, SKIL, and SMAD7.

[0136] It has been found by the present inventors that the genes in the successively shorter lists become more and more probative for determining the activity of the TGF-.beta. cellular signaling pathway.

Measuring Levels of Gene Expression

[0137] Data derived from the unique set of target genes described herein is further utilized to determine the activity level of the TGF-.beta. cellular signaling pathway using the methods described herein.

[0138] Methods for analyzing gene expression levels in isolated samples are generally known. For example, methods such as Northern blotting, the use of PCR, nested PCR, quantitative real-time PCR (qPCR), RNA-seq, or microarrays can all be used to derive gene expression level data. All methods known in the art for analyzing gene expression of the target genes are contemplated herein.

[0139] Methods of determining the expression product of a gene using PCR based methods may be of particular use. In order to quantify the level of gene expression using PCR, the amount of each PCR product of interest is typically estimated using conventional quantitative real-time PCR (qPCR) to measure the accumulation of PCR products in real time after each cycle of amplification. This typically utilizes a detectible reporter such as an intercalating dye, minor groove binding dye, or fluorogenic probe whereby the application of light excites the reporter to fluoresce and the resulting fluorescence is typically detected using a CCD camera or photomultiplier detection system, such as that disclosed in U.S. Pat. No. 6,713,297 which is hereby incorporated by reference.

[0140] In some embodiments, the probes used in the detection of PCR products in the quantitative real-time PCR (qPCR) assay can include a fluorescent marker. Numerous fluorescent markers are commercially available. For example, Molecular Probes, Inc. (Eugene, Oreg.) sells a wide variety of fluorescent dyes. Non-limiting examples include Cy5, Cy3, TAMRA, R6G, R110, ROX, JOE, FAM, Texas Red.TM., and Oregon Green.TM.. Additional fluorescent markers can include IDT ZEN Double-Quenched Probes with traditional 5' hydrolysis probes in qPCR assays. These probes can contain, for example, a 5' FAM dye with either a 3' TAMRA Quencher, a 3' Black Hole Quencher (BHQ, Biosearch Technologies), or an internal ZEN Quencher and 3' Iowa Black Fluorescent Quencher (IBFQ).

[0141] Fluorescent dyes useful according to the invention can be attached to oligonucleotide primers using methods well known in the art. For example, one common way to add a fluorescent label to an oligonucleotide is to react an N-Hydroxysuccinimide (NHS) ester of the dye with a reactive amino group on the target. Nucleotides can be modified to carry a reactive amino group by, for example, inclusion of an allyl amine group on the nucleobase. Labeling via allyl amine is described, for example, in U.S. Pat. Nos. 5,476,928 and 5,958,691, which are incorporated herein by reference. Other means of fluorescently labeling nucleotides, oligonucleotides and polynucleotides are well known to those of skill in the art.

[0142] Other fluorogenic approaches include the use of generic detection systems such as SYBR-green dye, which fluoresces when intercalated with the amplified DNA from any gene expression product as disclosed in U.S. Pat. Nos. 5,436,134 and 5,658,751 which are hereby incorporated by reference.

[0143] Another useful method for determining target gene expression levels includes RNA-seq, a powerful analytical tool used for transcriptome analyses, including gene expression level difference between different physiological conditions, or changes that occur during development or over the course of disease progression.

[0144] Another approach to determine gene expression levels includes the use of microarrays for example RNA and DNA microarray, which are well known in the art. Microarrays can be used to quantify the expression of a large number of genes simultaneously.

Calibrated Pathway Model

[0145] As contemplated herein, the expression levels of the unique set of target genes described herein are used to calculate the level TGF-.beta. transcription factor element using a calibrated pathway model as further described below. The calibrated pathway model compares the expression levels of the at least three target genes in the sample with expression levels of the at least three target genes in the calibrated pathway model which define a level of TGF-.beta. transcription factor element.

[0146] As contemplated herein, the calibrated pathway model is based on the application of a mathematical model. For example, the calibrated model can be based on a probabilistic model, for example a Bayesian network, or a linear or pseudo-linear model.

[0147] In one embodiment, the calibrated pathway model is a probabilistic model incorporating conditional probabilistic relationships that compare the expression levels of the at least three target genes in the sample with expression levels of the at least three target genes in the calibrated pathway model which define a level TGF-.beta. transcription factor element to determine the level of the TGF-.beta. transcription factor element in the sample. In one embodiment, the probabilistic model is a Bayesian network model.

[0148] In an alternative embodiment, the calibrated pathway model can be a linear or pseudo-linear model. In an embodiment, the linear or pseudo-linear model is a linear or pseudo-linear combination model.

[0149] A non-limiting exemplary flow chart for a calibrated pathway model is shown in FIG. 4. As an initial step, the training data for the mRNA expression levels is collected and normalized. The data can be collected using, for example microarray probeset intensities (101), real-time PCR Cq values (102), raw RNAseq reads (103), or alternative measurement modalities (104) known in the art. The raw expression level data can then be normalized for each method, respectively, by normalization using a normalization algorithm, for example, frozen robust military analysis (fRMA) or MAS5.0 (111), normalization to average Cq of reference genes (112), normalization of reads into reads/fragments per kilobase of transcript per million mapped reads (RPKM/FPKM) (113), or normalization to w.r.t. reference genes/proteins (114). This normalization procedure leads to a normalized probeset intensity (121), normalized Cq values (122), normalized RPKM/FPKM (123), or normalized measurement (124) for each method, respectively, which indicate target gene expression levels within the training samples.

[0150] Once the training data has been normalized, a training sample ID or IDs (131) is obtained and the training data of these specific samples is obtained from one of the methods for determining gene expression (132). The final gene expression results from the training sample are output as training data (133). All of the data from various training samples are incorporated to calibrate the model (including for example, thresholds, CPTs, for example in the case of the probabilistic or Bayesian network, weights, for example, in the case of the linear or pseudo-linear model, etc) (144). In addition, the pathway's target genes and measurement nodes (141) are used to generate the model structure for example, as described in FIG. 2 (142). The resulting model structure (143) of the pathway is then incorporated with the training data (133) to calibrate the model (144), wherein the gene expression levels of the target genes is indicative of the transcription factor element activity. As a result of the transcription factor element calculations in the training samples, a calibrated pathway model (145) is calculated which assigns the TGF-.beta. cellular signaling pathway activity level for a subsequently examined sample of interest, for example from a subject with a cancer, based on the target gene expression levels in the training samples.

Transcription Factor Element Calculation

[0151] A non-limiting exemplary flow chart for calculating the Transcription Factor Element activity level is provided in FIG. 5. The expression level data (test data) (163) from a sample isolated from a subject is input into the calibrated pathway model (145). The mathematical model may be a probabilistic model, for example a Bayesian network model, a linear model, or pseudo-linear model.

[0152] The mathematical model may be a probabilistic model, for example a Bayesian network model, based at least in part on conditional probabilities relating the TGF-.beta. TF element and expression levels of the one or more target gene(s) of the TGF-.beta. cellular signaling pathway measured in the sample of the subject, or the mathematical model may be based at least in part on one or more linear combination(s) of expression levels of the one or more target gene(s) of the TGF-.beta. cellular signaling pathway measured in the sample of the subject. In particular, the determining of the activity of the TGF-.beta. cellular signaling pathway may be performed as disclosed in the published international patent application WO 2013/011479 A2 ("Assessment of cellular signaling pathway activity using probabilistic modeling of target gene expression"), and incorporated herein by reference. Briefly, the data is entered into a Bayesian network (BN) inference engine call (for example, a BNT toolbox) (154). This leads to a set of values for the calculated marginal BN probabilities of all the nodes in the BN (155). From these probabilities, the transcription factor (TF) node's probability (156) is determined and establishes the TF's element activity level (157).

[0153] Alternatively, the mathematical model may be a linear model. For example, a linear model can be used as described in the published international patent application WO 2014/102668 A2 ("Assessment of cellular signaling pathway activity using linear combination(s) of target gene expressions"), the contents of which are herewith incorporated in their entirety. Further details regarding the calculating/determining of cellular signaling pathway activity using mathematical modeling of target gene expression can also be found in Verhaegh W. et al., "Selection of personalized patient therapy through the use of knowledge-based computational models that identify tumor-driving signal transduction pathways", Cancer Research, Vol. 74, No. 11, 2014, pages 2936 to 2945. Briefly, the data is entered into a calculated weighted linear combination score (w/c) (151). This leads to a set of values for the calculated weighted linear combination score (152). From these weighted linear combination scores, the transcription factor (TF) node's weighted linear combination score (153) is determined and establishes the TF's element activity level (157).

Procedure for Discretized Observables

[0154] A non-limiting exemplary flow chart for calculating the activity level of a TGF-.beta. cellular signaling pathway as a discretized observable is shown in FIG. 6. First, the test sample is isolated and given a test sample ID (161). Next, the test data for the mRNA expression levels is collected and normalized (162). The test data can be collected using the same methods as discussed for the training samples in FIG. 5, using microarray probeset intensities (101), real-time PCR Cq values (102), raw RNAseq reads (103), or an alternative measurement modalities (104). The raw expression level data can then be normalized for each method, respectively, by normalization using an algorithm, for example fRMA or MAS5.0 (111), normalization to average Cq of reference genes (112), normalization of reads into RPKM/FPKM (113), and normalization to w.r.t. reference genes/proteins (114). This normalization procedure leads to a normalized probeset intensity (121), normalized Cq values (122), normalized RPKM/FPKM (123), or normalized measurement (124) for each method, respectively.

[0155] Once the test data has been normalized, the resulting test data (163) is analyzed in a thresholding step (164) based on the calibrated pathway model (145), resulting in the thresholded test data (165). In using discrete observables, in one non-limiting example, every expression above a certain threshold is, for example, given a value of 1 and values below the threshold are given a value of 0, or in an alternative embodiment, the probability mass above the threshold as described herein is used as a thresholded value. Based on the calibrated pathway model, this value represents the TF's element activity level (157), which is then used to calculate the pathway's activity level (171). The final output gives the pathway's activity level (172) in the test sample being examined from the subject.

Procedure for Continuous Observables

[0156] A non-limiting exemplary flow chart for calculating the activity level of a TGF-.beta. cellular signaling pathway as a continuous observable is shown in FIG. 7. First, the test sample is isolated and given a test sample ID (161). Next, the test data for the mRNA expression levels is collected and normalized (162). The test data can be collected using the same methods as discussed for the training samples in FIG. 5, using microarray probeset intensities (101), real-time PCR Cq values (102), raw RNAseq reads (103), or an alternative measurement modalities (104). The raw expression level data can then be normalized for each method, respectively, by normalization using an algorithm, for example fRMA (111), normalization to average Cq of reference genes (112), normalization of reads into RPKM/FPKM (113), and normalization to w.r.t. reference genes/proteins (114). This normalization procedure leads to a a normalized probeset intensity (121), normalized Cq values (122), normalized RPKM/FPKM (123), or normalized measurement (124) for each method, respectively.

[0157] Once the test data has been normalized, the resulting test data (163) is analyzed in the calibrated pathway model (145). In using continuous observables, as one non-limiting example, the expression levels are converted to values between 0 and 1 using a sigmoid function as described in further detail below. The transcription factor element calculation as described herein is used to interpret the test data in combination with the calibrated pathway model, the resulting value represents the TF's element activity level (157), which is then used to calculate the pathway's activity level (171). The final output then gives the pathway's activity level (172) in the test sample.

Kits for Calculating TGF-.beta. Signaling Pathway Activity

[0158] In some embodiments, the present invention utilizes kits comprising primer and probe sets for the analyses of the expression levels of unique sets of target genes (See Target Gene discussion above). Particularly suitable oligo sequences for use as primers and probes for inclusion in a kit are described in the following text passages (see, e.g., Tables 1, 2, and 3).

[0159] Also contemplated herein is a kit comprising one or more components for measuring a set of unique TGF-.beta. target genes as described further below. In one non-limiting embodiment, the kit includes one or more components for measuring the expression levels of at least three target genes selected from ANGPTL4, and at least two of CDC42EP3, ID1, IL11, JUNB, SKIL, or SMAD7. In one embodiment, the at least three target genes are CDC42EP3, and at least two of ANGPTL4, ID1, IL11, JUNB, SKIL, or SMAD7. In one embodiment, the at least three target genes are ANGPTL4, and at least two of CDC42EP3, ID1, SERPINE1, JUNB, SKIL, or SMAD7. In one embodiment, the at least three target genes are CDC42EP3, and at least two of ANGPTL4, ID1, SERPINE1, JUNB, SKIL, or SMAD7. In one embodiment, the at least three target genes are ANGPTL4, CDC42EP3, and at least one of ID1, IL11, JUNB, SKIL, or SMAD7. In one embodiment, the at least three target genes are ANGPTL4, CDC42EP3, and at least one of ID1, SERPINE1, JUNB, SKIL, or SMAD7. In one embodiment, the kit includes one or more components for measuring the expression levels of the target genes ANGPTL4, CDC42EP3, ID1, IL11, JUNB, SKIL, and SMAD7. In one embodiment, the kit includes one or more components for measuring the expression levels of the target genes ANGPTL4, CDC42EP3, ID1, SERPINE1, JUNB, SKIL, and SMAD7.

[0160] In one embodiment, the kit includes one or more components for measuring the expression levels of at least three target genes, wherein the target genes are selected from ANGPTL4, CDC42EP3, ID1, SERPINE1, JUNB, SKIL, or SMAD7, and the one or more components is selected from the primers and probes listed in Table 1.

TABLE-US-00001 TABLE 1 Non-limiting example of primers and probes for a kit for measuring gene expression of TGF-.beta. target genes. SEQ Oligo Name Sequence 5'-3' ID No. Target Gene SMAD7_For1 TGCCTTCCTCCGCTGAAAC 72 SMAD7 SMAD7_Rev2 ACCACGCACCAGTGTGAC 73 SMAD7 SMAD7_probe1 TCCCAACTTCTTCTGGAGCCTGGG 74 SMAD7 SKIL_For1 GAAATGAAGGAGAAGTTTAGCA 75 SKIL SKIL_Rev1 GCTTTATAACAGGATACCATGAC 76 SKIL SKIL_Probe1 ACAGATGCACCATCAGGAATGGAATTACA 77 SKIL ID1_For2 TGAGGGAGAACAAGACCGAT 84 ID1 ID1_Revl ACTAGTAGGTGTGCAGAGA 85 ID1 ID1_Probe1 CACTGCGCCCTTAACTGCATCCA 86 ID1 ANGPTL4_For3 GCGAATTCAGCATCTGCAAAG 87 ANGPTL4 ANGPTL4_Rev4 CTTTCTTCGGGCAGGCTT 88 ANGPTL4 ANGPTL4_Probe2 ACCACAAGCACCTAGACCATGAGGT 89 ANGPTL4 CDC42EP3_For1 TGTGGTCAAGACTGGATGATG 93 CDCCDC42EP3 CDC42EP3_Rev1 CAGAAGTGGCTTCGAAATGA 94 CDCCDC42EP3 CDC42EP3_Probe1 TCTCTAGGAAGCCTCACTTGGCCG 95 CDCCDC42EP3 JUNB_For2 AATGGAACAGCCCTTCTACCA 96 JUNB JUNB_Rev1 GCTCGGTTTCAGGAGTTTGTA 97 JUNB JUNB_Probe1 TCATACACAGCTACGGGATACGG 98 JUNB SERPINE1_For1 CCACAAATCAGACGGCAGCA 105 SERPINE1 SERPINE1_Rev1 GTCGTAGTAATGGCCATCGG 106 SERPINE1 SERPINE1_Probe1 CCCATGATGGCTCAGACCAACAAGT 107 SERPINE1

[0161] In one embodiment, the kit includes one or more components for measuring the expression levels of at least three target genes, wherein the target genes are selected from ANGPTL4, and at least two of CDC42EP3, ID1, SERPINE1, JUNB, SKIL, or SMAD7, and the one or more components is selected from the primers and probes listed in Table 1. In one embodiment, the kit includes one or more components for measuring the expression levels of at least three target genes, wherein the target genes are CDC42EP3, and at least two of ANGPTL4, ID1, SERPINE1, JUNB, SKIL, or SMAD7, and the one or more components is selected from the PCR primers and probes listed in Table 1. In another embodiment, the kit includes one or more components for measuring the expression levels of at least three target genes, wherein the target genes are ANGPTL4, CDC42EP3, and at least one of ID1, SERPINE1, JUNB, SKIL, or SMAD7, and the one or more components is selected from the PCR primers and probes listed in Table 1. In one embodiment, the kit includes one or more components for measuring the expression levels of the target genes ANGPTL4, CDC42EP3, ID1, SERPINE1, JUNB, SKIL, and SMAD7, and the one or more components is selected from the PCR primers and probes listed in Table 1.

[0162] In one embodiment, the kit includes one or more components for measuring the expression level of at least one additional target gene selected from CDKN1A, CTGF, GADD45B, PDGFB, and SNAI2. In one embodiment, the kit includes one or more components for measuring the expression level of at least one additional target gene selected from CDKN1A, CTGF, GADD45B, VEGFA, and SNAI2. In one embodiment, the kit includes one or more components for measuring the expression levels of target genes ANGPTL4, CDC42EP3, ID1, IL11, JUNB, SKIL, SMAD7, CDKN1A, CTGF, GADD45B, PDGFB, and SNAI2.

[0163] In one embodiment, the kit includes one or more components for measuring the expression levels of target genes ANGPTL4, CDC42EP3, ID1, SERPINE1, JUNB, SKIL, SMAD7, CDKN1A, CTGF, GADD45B, VEGFA, and SNAI2. In one non-limiting embodiment, the kit includes one or more components for measuring the expression levels of target genes ANGPTL4, CDC42EP3, ID1, SERPINE1, JUNB, SKIL, SMAD7, CDKN1A, CTGF, GADD45B, VEGFA, and SNAI2, wherein the one or more components includes the PCR primers and probes listed in Table 2. The PCR primers for each gene are designated Forward (For) and Reverse (Rev) and the probes for detection of the PCR products for each gene are labeled Probe. In one non-limiting embodiment, the probes listed in Table 2 are labeled with a 5' FAM dye with an internal ZEN Quencher and 3' Iowa Black Fluorescent Quencher (IBFQ).

TABLE-US-00002 TABLE 2 Oligo Sequences for Target Genes SEQ Oligo Name Sequence 5'-3' ID No. Target Gene SMAD7_For1 TGCCTTCCTCCGCTGAAAC 72 SMAD7 SMAD7_Rev2 ACCACGCACCAGTGTGAC 73 SMAD7 SMAD7_probe1 TCCCAACTTCTTCTGGAGCCTGGG 74 SMAD7 SKIL_For1 GAAATGAAGGAGAAGTTTAGCA 75 SKIL SKIL_Rev1 GCTTTATAACAGGATACCATGAC 76 SKIL SKIL_Probe1 ACAGATGCACCATCAGGAATGGAATTACA 77 SKIL CTGF_For1 GAAGCTGACCTGGAAGAGAA 78 CTGF CTGF_Rev1 CCACAGAATTTAGCTCGGTATG 79 CTGF CTGF_Probe2 CCTATCAAGTTTGAGCTTTCTGGCTG 80 CTGF CDKN1A_For1 GAGACTCTCAGGGTCGAAA 81 CDKN1A CDKN1A_Rev2 CTGTGGGCGGATTAGGGCT 82 CDKN1A CDKN1A_Probe1 ATTTCTACCACTCCAAACGCCGGC 83 CDKN1A ID1_For2 TGAGGGAGAACAAGACCGAT 84 ID1 ID1_Rev1 ACTAGTAGGTGTGCAGAGA 85 ID1 ID1_Probe1 CACTGCGCCCTTAACTGCATCCA 86 ID1 ANGPTL4_For3 GCGAATTCAGCATCTGCAAAG 87 ANGPTL4 ANGPTL4_Rev4 CTTTCTTCGGGCAGGCTT 88 ANGPTL4 ANGPTL4_Probe2 ACCACAAGCACCTAGACCATGAGGT 89 ANGPTL4 GADD45B_For1 GTCGGCCAAGTTGATGAATG 90 GADD45B GADD45B_Rev1 GATGAGCGTGAAGTGGATTTG 91 GADD45B GADD45B_probe1 CCATTGACGAGGAGGAGGAGGAT 92 GADD45B CDC42EP3_For1 TGTGGTCAAGACTGGATGATG 93 CDC42EP3 CDC42EP3_Rev1 CAGAAGTGGCTTCGAAATGA 94 CDC42EP3 CDC42EP3_Probe1 TCTCTAGGAAGCCTCACTTGGCCG 95 CDC42EP3 JUNB_For2 AATGGAACAGCCCTTCTACCA 96 JUNB JUNB_Rev1 GCTCGGTTTCAGGAGTTTGTA 97 JUNB JUNB_Probe1 TCATACACAGCTACGGGATACGG 98 JUNB SNAI2_For1 GTTGCTTCAAGGACACATTAG 99 SNAI2 SNAI2_Rev1 GCAGATGAGCCCTCAGATTT 100 SNAI2 SNAI2_Probe1 TGCCCTCACTGCAACAGAGCATTT 101 SNAI2 VEGFA_For1 GAAGGAGGAGGGCAGAATC 102 VEGFA VEGFA_Rev1 GTCTCGATTGGATGGCAGTA 103 VEGFA VEGFA_Probe1 AGTTCATGGATGTCTATCAGCGCAGC 104 VEGFA SERPINE1_For1 CCACAAATCAGACGGCAGCA 105 SERPINE1 SERPINE1_Revl GTCGTAGTAATGGCCATCGG 106 SERPINE1 SERPINE1_Probe1 CCCATGATGGCTCAGACCAACAAGT 107 SERPINE1

[0164] In one non-limiting embodiment, the kit includes one or more components for measuring the expression levels of control genes, wherein the one or more components includes a PCR primer set and probe for at least one of the control genes listed in Table 3. The PCR primers for each gene are designated Forward (F) and Reverse (R) and the probes for detection of the PCR products for each gene are labeled Probe (P or FAM). In one non-limiting embodiment, the probes listed in Table 3 are labeled with a 5' FAM dye with an internal ZEN Quencher and 3' Iowa Black Fluorescent Quencher (IBFQ).

TABLE-US-00003 TABLE 3 Oligo Sequences for Controls Reference Oligo Name Sequence 5'-3' SEQ ID No. gene Hum_BACT_F1 CCAACCGCGAGAAGATGA 108 ACTB Hum_BACT_R1 CCAGAGGCGTACAGGGATAG 109 ACTB Hum_BACT_P1 CCATGTACGTTGCTATCCAGGCT 110 ACTB Hum_POLR2A_F1 AGTCCTGAGTCCGGATGAA 111 POLR2A Hum_POLR2A_R1 CCTCCCTCAGTCGTCTCT 112 POLR2A Hum_POLR2A_P1 TGACGGAGGGTGGCATCAAATACC 113 POLR2A Hum_PUM1_F2 GCCAGCTTGTCTTCAATGAAAT 114 PUM1 Hum_PUM1_R2 CAAAGCCAGCTTCTGTTCAAG 115 PUM1 Hum_PUM1_P1 ATCCACCATGAGTTGGTAGGCAGC 116 PUM1 Hum_TBP_F1 GCCAAGAAGAAAGTGAACATCAT 117 TBP Hum_TBP1_R1 ATAGGGATTCCGGGAGTCAT 118 TBP Hum_TBP_P1 TCAGAACAACAGCCTGCCACCTTA 119 TBP K-ALPHA-1_F1 TGACTCCTTCAACACCTTCTTC 120 TUBA1B K-ALPHA-1_R1 TGCCAGTGCGAACTTCAT 121 TUBA1B K-ALPHA-1_FAM1 CCGGGCTGTGTTTGTAGACTTGGA 122 TUBA1B ALAS1_F1 AGCCACATCATCCCTGT 123 ALAS1 ALAS1_R1 CGTAGATGTTATGTCTGCTCAT 124 ALAS1 ALAS1_FAM1 TTTAGCAGCATCTGCAACCCGC 125 ALAS1 Hum_HPRT1_Fl GAGGATTTGGAAAGGGTGTTTATT 126 HPRT1 Hum_HPRT1_R1 ACAGAGGGCTACAATGTGATG 127 HPRT1 Hum_HPRT1_P1 ACGTCTTGCTCGAGATGTGATGAAGG 128 HPRT1 Hum_RPLP0_F2 TAAACCCTGCGTGGCAAT 129 RPLPO Hum_RPLP0_R2 ACATTTCGGATAATCATCCAATAGTTG 130 RPLPO Hum_RPLP0_P1 AAGTAGTTGGACTTCCAGGTCGCC 131 RPLPO Hum_B2M_F1 CCGTGGCCTTAGCTGTG 132 B2M Hum_B2M_R1 CTGCTGGATGACGTGAGTAAA 133 B2M Hum_B2M_P1 TCTCTCTTTCTGGCCTGGAGGCTA 134 B2M TPT1_F_PACE AAATGTTAACAAATGTGGCAATTAT 135 TPT1 TPT1_R_PACE AACAATGCCTCCACTCCAAA 136 TPT1 TPT1_P_PACE TCCACACAACACCAGGACTT 137 TPT1 EEF1A1_F_PACE TGAAAACTACCCCTAAAAGCCA 138 EEF1A1 EEF1A1_R_PACE TATCCAAGACCCAGGCATACT 139 EEF1A1 EEF1A1_P_PACE TAGATTCGGGCAAGTCCACCA 140 EEF1A1 RPL41_F_PACE AAGATGAGGCAGAGGTCCAA 141 RPL41 RPL41_R_PACE TCCAGAATGTCACAGGTCCA 142 RPL41 RPL41_P_PACE TGCTGGTACAAGTTGTGGGA 143 RPL41

[0165] As contemplated herein, the one or more components for measuring the expression levels of the particular target genes can be selected from the group consisting of: an DNA array chip, an oligonucleotide array chip, a protein array chip, an antibody, a plurality of probes, for example, labeled probes, a set of RNA reverser-transcriptase sequencing components, and/or RNA or DNA, including cDNA, amplification primers. In one embodiment, the kit includes a set of labeled probes directed to the cDNA sequence of the targeted genes as described herein contained in a standardized 96-well plate. In one embodiment, the kit further includes a non-transitory storage medium containing instructions that are executable by a digital processing device to perform a method according to the present invention as described herein.

[0166] In accordance with another disclosed aspect, a kit for measuring expression levels of one or more, two or more, or at least three, target gene(s) of the TGF-.beta. cellular signaling pathway in a sample of a subject comprises:

[0167] one or more components for determining the expression levels of the one or more, two or more, or at least three, target gene(s) of the TGF-.beta. cellular signaling pathway,

[0168] wherein the one or more components are, for example, selected from the group consisting of: an DNA array chip, an oligonucleotide array chip, a protein array chip, an antibody, a plurality of probes, RNA sequencing and a set of primers, and

[0169] wherein the one or more, two or more, or at least three, target gene(s) of the TGF-.beta. cellular signaling pathway is/are selected from the group consisting of: ANGPTL4, CDC42EP3, CDKN1A, CDKN2B, CTGF, GADD45A, GADD45B, HMGA2, ID1, IL11, INPP5D, JUNB, MMP2, MMP9, NKX2-5, OVOL1, PDGFB, PTHLH, SGK1, SKIL, SMAD4, SMAD5, SMAD6, SMAD7, SNAIL SNAI2, TIMP1, and VEGFA, or ANGPTL4, CDC42EP3, CDKN1A, CDKN2B, CTGF, GADD45A, GADD45B, HMGA2, ID1, IL11, SERPINE1, INPP5D, JUNB, MMP2, MMP9, NKX2-5, OVOL1, PDGFB, PTHLH, SGK1, SKIL, SMAD4, SMAD5, SMAD6, SMAD7, SNAIL SNAI2, TIMP1, and VEGFA, or from the group consisting of: ANGPTL4, CDC42EP3, CDKN1A, CTGF, GADD45A, GADD45B, HMGA2, ID1, IL11, JUNB, PDGFB, PTHLH, SGK1, SKIL, SMAD4, SMAD5, SMAD6, SMAD7, SNAI2, and VEGFA or ANGPTL4, CDC42EP3, CDKN1A, CTGF, GADD45A, GADD45B, HMGA2, ID1, SERPINE1, JUNB, PDGFB, PTHLH, SGK1, SKIL, SMAD4, SMAD5, SMAD6, SMAD7, SNAI2, and VEGFA, or from the group consisting of: ANGPTL4, CDC42EP3, CDKN1A, CTGF, GADD45B, ID1, IL11, JUNB, PDGFB, SKIL, SMAD7, and SNAI2, or ANGPTL4, CDC42EP3, CDKN1A, CTGF, GADD45B, ID1, SERPINE1, JUNB, VEGFA, SKIL, SMAD7, and SNAI2, or from the group consisting of: ANGPTL4, CDC42EP3, ID1, IL11, JUNB, SKIL, and SMAD7, or ANGPTL4, CDC42EP3, ID1, SERPINE1, JUNB, SKIL, and SMAD7.

[0170] In accordance with another disclosed aspect, a kit for measuring expression levels of two, three or more target genes of a set of target genes of the TGF-.beta. cellular signaling pathway in a sample of a subject comprises:

[0171] one or more components for determining the expression levels of the two, three or more target genes of the set of target genes of the TGF-.beta. cellular signaling pathway,

[0172] wherein the one or more components are, for example, selected from the group consisting of: an DNA array chip, an oligonucleotide array chip, a protein array chip, an antibody, a plurality of probes, RNA sequencing and a set of primers.

[0173] In one embodiment,

[0174] the set of target genes of the TGF-.beta. cellular signaling pathway includes at least seven, or in an alternative, all target genes selected from the group consisting of: ANGPTL4, CDC42EP3, CDKN1A, CDKN2B, CTGF, GADD45A, GADD45B, HMGA2, ID1, IL11, INPP5D, JUNB, MMP2, MMP9, NKX2-5, OVOL1, PDGFB, PTHLH, SGK1, SKIL, SMAD4, SMAD5, SMAD6, SMAD7, SNAIL SNAI2, TIMP1, and VEGFA, or ANGPTL4, CDC42EP3, CDKN1A, CDKN2B, CTGF, GADD45A, GADD45B, HMGA2, ID1, IL11, SERPINE1, INPP5D, JUNB, MMP2, MMP9, NKX2-5, OVOL1, PDGFB, PTHLH, SGK1, SKIL, SMAD4, SMAD5, SMAD6, SMAD7, SNAIL SNAI2, TIMP1, and VEGFA, or from the group consisting of: ANGPTL4, CDC42EP3, CDKN1A, CTGF, GADD45A, GADD45B, HMGA2, ID1, IL11, JUNB, PDGFB, PTHLH, SGK1, SKIL, SMAD4, SMAD5, SMAD6, SMAD7, SNAI2, and VEGFA, or ANGPTL4, CDC42EP3, CDKN1A, CTGF, GADD45A, GADD45B, HMGA2, ID1, SERPINE1, JUNB, PDGFB, PTHLH, SGK1, SKIL, SMAD4, SMAD5, SMAD6, SMAD7, SNAI2, and VEGFA, or from the group consisting of: ANGPTL4, CDC42EP3, CDKN1A, CTGF, GADD45B, ID1, IL11, JUNB, PDGFB, SKIL, SMAD7, and SNAI2, or ANGPTL4, CDC42EP3, CDKN1A, CTGF, GADD45B, ID1, SERPINE1, JUNB, VEGFA, SKIL, SMAD7, and SNAI2, or from the group consisting of: ANGPTL4, CDC42EP3, ID1, IL11, JUNB, SKIL, and SMAD7, or ANGPTL4, CDC42EP3, ID1, SERPINE1, JUNB, SKIL, and SMAD7.

[0175] In one embodiment, the PCR cycling is performed in a microtiter or multi-well plate format. This format, which uses plates comprising multiple reaction wells, not only increases the throughput of the assay process, but is also well adapted for automated sampling steps due to the modular nature of the plates and the uniform grid layout of the wells on the plates. Common microtiter plate designs useful according to the invention have, for example 12, 24, 48, 96, 384, or more wells, although any number of wells that physically fit on the plate and accommodate the desired reaction volume (usually 10-100 .mu.l) can be used according to the invention. Generally, the 96 or 384 well plate format can be utilized. In one embodiment, the method is performed in a 96 well plate format. In one embodiment, the method is performed in a 384 well plate format.

[0176] The present invention includes kits for measuring gene expression. Provided herein is a kit for measuring expression levels of two, three or more target genes of a set of target genes of the TGF-.beta. cellular signaling pathway in a sample of a subject, comprising: one or more components for determining the expression levels of the two, three or more target genes of the set of target genes of the TGF-.beta. cellular signaling pathway, wherein the set of target genes of the TGF-.beta. cellular signaling pathway includes at least seven, or, in an alternative, all target genes selected from the group consisting of: ANGPTL4, CDC42EP3, CDKN1A, CDKN2B, CTGF, GADD45A, GADD45B, HMGA2, ID1, IL11, INPP5D, JUNB, MMP2, MMP9, NKX2-5, OVOL1, PDGFB, PTHLH, SGK1, SKIL, SMAD4, SMAD5, SMAD6, SMAD7, SNAIL SNAI2, TIMP1, and VEGFA, or ANGPTL4, CDC42EP3, CDKN1A, CDKN2B, CTGF, GADD45A, GADD45B, HMGA2, ID1, IL11, SERPINE1, INPP5D, JUNB, MMP2, MMP9, NKX2-5, OVOL1, PDGFB, PTHLH, SGK1, SKIL, SMAD4, SMAD5, SMAD6, SMAD7, SNAIL SNAI2, TIMP1, and VEGFA, or from the group consisting of: ANGPTL4, CDC42EP3, CDKN1A, CTGF, GADD45A, GADD45B, HMGA2, ID1, IL11, JUNB, PDGFB, PTHLH, SGK1, SKIL, SMAD4, SMAD5, SMAD6, SMAD7, SNAI2, and VEGFA, or ANGPTL4, CDC42EP3, CDKN1A, CTGF, GADD45A, GADD45B, HMGA2, ID1, SERPINE1, JUNB, PDGFB, PTHLH, SGK1, SKIL, SMAD4, SMAD5, SMAD6, SMAD7, SNAI2, and VEGFA, or from the group consisting of: ANGPTL4, CDC42EP3, CDKN1A, CTGF, GADD45B, ID1, IL11, JUNB, PDGFB, SKIL, SMAD7, and SNAI2, or ANGPTL4, CDC42EP3, CDKN1A, CTGF, GADD45B, ID1, SERPINE1, JUNB, VEGFA, SKIL, SMAD7, and SNAI2, or from the group consisting of: ANGPTL4, CDC42EP3, ID1, IL11, JUNB, SKIL, and SMAD7, or ANGPTL4, CDC42EP3, ID1, SERPINE1, JUNB, SKIL, and SMAD7.

[0177] In one embodiment, the kit comprises an apparatus comprising a digital processor. In another embodiment, the kit comprises a non-transitory storage medium storing instructions that are executable by a digital processing device. In yet another embodiment, the kit comprises a computer program comprising program code means for causing a digital processing device to perform the methods described herein.

[0178] In an additional embodiment, the kit contains one or more components that are for example selected from the group consisting of: a DNA array chip, an oligonucleotide array chip, a protein array chip, an antibody, a plurality of probes, RNA sequencing and a set of primers. In one embodiment, the kit contains a plurality of probes. In one embodiment, the kit contains a set of primers. In one embodiment, the kit contains a 6, 12, 24, 48, 96, or 384-well PCR plate. In one embodiment, the kit includes a 96 well PCR plate. In one embodiment, the kit includes a 384 well PCR plate.

[0179] In one embodiment, the kit for measuring the expression levels of TGF-.beta. cellular signaling pathway genes comprises a means for measuring the expression levels of a set of TGF-.beta. cellular signaling pathway genes, wherein the genes consist of ANGPTL4, and at least two of CDC42EP3, ID1, SERPINE1, JUNB, SKIL, or SMAD7. In one embodiment, the kit for measuring the expression levels of TGF-.beta. cellular signaling pathway genes comprises a means for measuring the expression levels of a set of TGF-.beta. cellular signaling pathway genes, wherein the genes consist of ANGPTL4, CDC42EP3, and at least one of ID1, SERPINE1, JUNB, SKIL, or SMAD7. In one embodiment, the kit for measuring the expression levels of TGF-.beta. cellular signaling pathway genes comprises a means for measuring the expression levels of a set of TGF-13 cellular signaling pathway genes, wherein the genes consist of ANGPTL4, CDC42EP3, ID1, SERPINE1, JUNB, SKIL, and SMAD7. In another embodiment, the genes further consist of at least one additional gene selected from CDKN1A, CTGF, GADD45B, PDGFB, and SNAI2. In another embodiment, the genes further consist of CDKN1A, CTGF, GADD45B, PDGFB, and SNAI2. In a further embodiment, the genes further consist of at least one additional gene selected from GADD45A, HMGA2, PTHLH, SGK1, SMAD4, SMAD5, SMAD6, SMAD7, and VEGFA. In a further embodiment, the genes further consist of GADD45A, HMGA2, PTHLH, SGK1, SMAD4, SMAD5, SMAD6, SMAD7, and VEGFA. In a further embodiment, the genes further consist of at least one additional gene selected from INPP5D, MMP2, MMP9, NKX2-5, OVOL1, and TIMP1. In a further embodiment, the genes further consist of INPP5D, MMP2, MMP9, NKX2-5, OVOL1, and TIMP1.

[0180] In one embodiment, a kit for measuring the expression levels of TGF-.beta. cellular signaling target genes comprises a 96-well plate and a set of labeled probes for detecting expression of a set of TGF-.beta. cellular signaling pathway genes comprising ANGPTL4, CDC42EP3, ID1, SERPINE1, JUNB, SKIL, or SMAD7. In one embodiment, a kit for measuring the expression levels of TGF-.beta. cellular signaling target genes comprises a 96-well plate and a set of labeled probes for detecting expression of a set of TGF-.beta. cellular signaling pathway genes comprising ANGPTL4, CDC42EP3, and at least one of ID1, SERPINE1, JUNB, SKIL, or SMAD7. In one embodiment, a kit for measuring the expression levels of TGF-.beta. cellular signaling target genes comprises a 96-well plate and a set of labeled probes for detecting expression of a set of TGF-.beta. cellular signaling pathway genes comprising ANGPTL4, CDC42EP3, ID1, SERPINE1, JUNB, SKIL, and SMAD7. In another embodiment, the genes further consist of at least one additional gene selected from CDKN1A, CTGF, GADD45B, PDGFB, and SNAI2. In another embodiment, the genes further consist of CDKN1A, CTGF, GADD45B, PDGFB, and SNAI2. In a further embodiment, the genes further consist of at least one additional gene selected from GADD45A, HMGA2, PTHLH, SGK1, SMAD4, SMAD5, SMAD6, SMAD7, and VEGFA. In a further embodiment, the genes further consist of GADD45A, HMGA2, PTHLH, SGK1, SMAD4, SMAD5, SMAD6, SMAD7, and VEGFA. In a further embodiment, the genes further consist of at least one additional gene selected from INPP5D, MMP2, MMP9, NKX2-5, OVOL1, and TIMP1. In a further embodiment, the genes further consist of INPP5D, MMP2, MMP9, NKX2-5, OVOL1, and TIMP1.

[0181] In one embodiment, the kit further comprises an instruction manual measuring the expression levels of TGF-.beta. cellular signaling target genes. In another embodiment, the kit further comprises an access code to access a computer program code for calculating the TGF-.beta. cellular signaling pathway activity in the sample. In a further embodiment, the kit further comprises an access code to access a website for calculating the TGF-.beta. cellular signaling pathway activity in the sample according to the methods described above.

Target Gene Expression Level Determination Procedure

[0182] A non-limiting exemplary flow chart for deriving target gene expression levels from a sample isolated from a subject is shown in FIG. 8. In one exemplary embodiment, samples are received and registered in a laboratory. Samples can include, for example, Formalin-Fixed, Paraffin-Embedded (FFPE) samples (181) or fresh frozen (FF) samples (180). FF samples can be directly lysed (183). For FFPE samples, the paraffin can be removed with a heated incubation step upon addition of Proteinase K (182). Cells are then lysed (183), which destroys the cell and nuclear membranes which makes the nucleic acid (NA) available for further processing. The nucleic acid is bound to a solid phase (184) which could for example, be beads or a filter. The nucleic acid is then washed with washing buffers to remove all the cell debris which is present after lysis (185). The clean nucleic acid is then detached from the solid phase with an elution buffer (186). The DNA is removed by DNAse treatment to ensure that only RNA is present in the sample (187). The nucleic acid sample can then be directly used in the RT-qPCR sample mix (188). The RT-qPCR sample mixes contains the RNA sample, the RT enzyme to prepare cDNA from the RNA sample and a PCR enzyme to amplify the cDNA, a buffer solution to ensure functioning of the enzymes and can potentially contain molecular grade water to set a fixed volume of concentration. The sample mix can then be added to a multiwell plate (i.e., 96 well or 384 well plate) which contains dried RT-qPCR assays (189). The RT-qPCR can then be run in a PCR machine according to a specified protocol (190). An example PCR protocol includes i) 30 minutes at 50.degree. C.; ii) 5 minutes at 95.degree. C.; iii) 15 seconds at 95.degree. C.; iv) 45 seconds at 60.degree. C.; v) 50 cycles repeating steps iii and iv. The Cq values are then determined with the raw data by using the second derivative method (191). The Cq values are exported for analysis (192).

Computer Programs and Computer Implemented Methods

[0183] As contemplated herein, the calculation of TGF-.beta. signaling in the sample is performed on a computerized device having a processor capable of executing a readable program code for calculating the TGF-.beta. cellular signaling pathway activity in the sample according to the methods described above. Accordingly, the computerized device can include means for receiving expression level data, wherein the data is expression levels of at least three target genes derived from the sample, a means for calculating the level of TGF-.beta. transcription factor element in the sample using a calibrated pathway model, wherein the calibrated pathway model compares the expression levels of the at least three target genes in the sample with expression levels of the at least three target genes in the model which have been correlated with a level TGF-.beta. transcription factor element; a means for calculating the TGF-.beta. cellular signaling in the sample based on the calculated levels of TGF-.beta. transcription factor element in the sample; and a means for assigning a TGF-.beta. cellular signaling pathway activity probability or status to the calculated TGF-.beta. cellular signaling in the sample, and a means for displaying the TGF-.beta. signaling pathway activity probability or status.

[0184] In accordance with another disclosed aspect, a non-transitory storage medium stores instructions that are executable by a digital processing device to perform a method according to the present invention as described herein. The non-transitory storage medium may be a computer-readable storage medium, such as a hard drive or other magnetic storage medium, an optical disk or other optical storage medium, a random access memory (RAM), read only memory (ROM), flash memory, or other electronic storage medium, a network server, or so forth. The digital processing device may be a handheld device (e.g., a personal data assistant or smartphone), a notebook computer, a desktop computer, a tablet computer or device, a remote network server, or so forth.

[0185] In accordance with another disclosed aspect, an apparatus comprises a digital processor configured to perform a method according to the present invention as described herein.

[0186] In accordance with another disclosed aspect, a computer program comprises program code means for causing a digital processing device to perform a method according to the present invention as described herein. The digital processing device may be a handheld device (e.g., a personal data assistant or smartphone), a notebook computer, a desktop computer, a tablet computer or device, a remote network server, or so forth.

[0187] In one embodiment, a computer program or system is provided for predicting the activity status of a TGF-.beta. transcription factor element in a human cancer sample that includes a means for receiving data corresponding to the expression level of one or more TGF-.beta. target genes in a sample from a host. In some embodiments, a means for receiving data can include, for example, a processor, a central processing unit, a circuit, a computer, or the data can be received through a website.

[0188] In one embodiment, a computer program or system is provided for predicting the activity status of a TGF-.beta. transcription factor element in a human cancer sample that includes a means for displaying the TGF-.beta. pathway signaling status in a sample from a host. In some embodiments, a means for displaying can include a computer monitor, a visual display, a paper print out, a liquid crystal display (LCD), a cathode ray tube (CRT), a graphical keyboard, a character recognizer, a plasma display, an organic light-emitting diode (OLED) display, or a light emitting diode (LED) display, or a physical print out.

[0189] In accordance with another disclosed aspect, a signal represents a determined activity of a TGF-.beta. cellular signaling pathway in a subject, wherein the determined activity results from performing a method according to the present invention as described herein. The signal can be a digital signal or it can be an analog signal.

[0190] In one aspect of the present invention, a computer implemented method is provided for predicting the activity status of a TGF-.beta. signaling pathway in a human cancer sample performed by a computerized device having a processor comprising: a) calculating an activity level of a TGF-.beta. transcription factor element in a human cancer sample, wherein the level of the TGF-.beta. transcription factor element in the human cancer sample is associated with the activity of a TGF-.beta. cellular signaling pathway, and wherein the level of the TGF-.beta. transcription factor element in the human cancer sample is calculated by i) receiving data on the expression levels of at least three target genes derived from the human cancer sample, wherein the TGF-.beta. transcription factor controls transcription of the at least three target genes, and wherein the at least three target genes are ANGPTL4, and at least two of CDC42EP3, ID1, IL11, JUNB, SKIL, or SMAD7 ii) calculating the activity level of the TGF-.beta. transcription factor element in the human cancer sample using a calibrated pathway model, wherein the calibrated pathway model compares the expression levels of the at least three target genes in the human cancer sample with expression levels of the at least three target genes in the model which have been correlated with an activity level of a TGF-.beta. transcription factor element; b) calculating the TGF-.beta. cellular signaling pathway activity in the human cancer sample based on the calculated TGF-.beta. transcription factor element activity level in the human cancer sample; c) assigning a TGF-.beta. cellular signaling pathway activity status to the TGF-.beta. cellular signaling pathway in the human cancer sample, wherein the activity status is indicative of either an active TGF-.beta. cellular signaling pathway or a passive TGF-.beta. cellular signaling pathway; and d) displaying the TGF-.beta. signaling pathway activity status.

[0191] In one aspect of the invention, a system is provided for determining the activity level of a TGF-.beta. cellular signaling pathway in a subject comprising a) a processor capable of calculating an activity level of TGF-.beta. transcription factor element in a sample derived from the subject; b) a means for receiving data, wherein the data is an expression level of at least three target genes derived from the sample; c) a means for calculating the level of the TGF-.beta. transcription factor element in the sample using a calibrated pathway model, wherein the calibrated pathway model compares the expression levels of the at least three target genes in the sample with expression levels of the at least three target genes in the model which define an activity level of TGF-.beta. transcription factor element; d) a means for calculating the activity level of the TGF-.beta. cellular signaling pathway in the sample based on the calculated activity level of TGF-.beta. transcription factor element in the sample; a means for assigning a TGF-.beta. cellular signaling pathway activity status to the calculated activity level of the TGF-.beta. cellular signaling pathway in the sample, wherein the activity status is indicative of either an active TGF-.beta. cellular signaling pathway or a passive TGF-.beta. cellular signaling pathway; and f) a means for displaying the TGF-.beta. signaling pathway activity status.

TGF-.beta. Mediated Diseases and Disorders and Methods of Treatment

[0192] As contemplated herein, the methods and apparatuses of the present invention can be utilized to assess TGF-.beta. cellular signaling pathway activity in a subject, for example a subject suspected of having, or having, a disease or disorder wherein the status of the TGF-.beta. signaling pathway is probabtive, either wholly or partially, of disease presence or progression. In one embodiment, provided herein is a method of treating a subject comprising receiving information regarding the activity status of a TGF-.beta. cellular signaling pathway derived from a sample isolated from the subject using the methods described herein and administering to the subject a TGF-.beta. inhibitor if the information regarding the level of TGF-.beta. cellular signaling pathway is indicative of an active TGF-.beta. signaling pathway. In a particular embodiment, the TGF-.beta. cellular signaling pathway activity indication is set at a cutoff value of odds of the TGF-B cellular signaling pathway being active of 10:1, 5:1, 4:1, 2:1, 1:1, 1:2, 1:4, 1:5, 1:10. TGF-.beta. inhibitors are known and include, but are not limtied to, Terameprocol, Fresolimumab, Sotatercept, Galunisertib, SB431542, LY2109761, LDN-193189, SB525334, SB505124, GW788388, LY364947, RepSox, LDN-193189 HCl, K02288, LDN-214117, SD-208, EW-7197, ML347, LDN-212854, DMH1, Pirfenidone, Hesperetin, Trabedersen, Lerdelimumab, Metelimumab, trx-SARA, ID11, Ki26894, or SB-431542.

[0193] In one embodiment, the disease or disorder is one of an auto-immune and other immune disorders, cancer, bronchial asthma, heart disease, diabetes, hereditary hemorrhagic telangiectasia, Marfan syndrome, Vascular Ehlers-Danlos syndrome, Loeys-Dietz syndrome, Parkinson's disease, Chronic kidney disease, Multiple Sclerosis, fibrotic diseases such as liver, lng, or kidney fibrosis, Dupuytren's disease, or Alzheimer's disease.

[0194] In a particular embodiment, the subject is suffering from, or suspected to have, a cancer, for example, but not limited to, a primary tumor or a metastatic tumor, a solid tumor, for example, melanoma, lung cancer (including lung adenocarcinoma, basal cell carcinoma, squamous cell carcinoma, large cell carcinoma, bronchioloalveolar carcinoma, bronchiogenic carcinoma, non-small-cell carcinoma, small cell carcinoma, mesothelioma); breast cancer (including ductal carcinoma, lobular carcinoma, inflammatory breast cancer, clear cell carcinoma, mucinous carcinoma, serosal cavities breast carcinoma); colorectal cancer (colon cancer, rectal cancer, colorectal adenocarcinoma); anal cancer; pancreatic cancer (including pancreatic adenocarcinoma, islet cell carcinoma, neuroendocrine tumors); prostate cancer; prostate adenocarcinoma; ovarian carcinoma (ovarian epithelial carcinoma or surface epithelial-stromal tumor including serous tumor, endometrioid tumor and mucinous cystadenocarcinoma, sex-cord-stromal tumor); liver and bile duct carcinoma (including hepatocellular carcinoma, cholangiocarcinoma, hemangioma); esophageal carcinoma (including esophageal adenocarcinoma and squamous cell carcinoma); oral and oropharyngeal squamous cell carcinoma; salivary gland adenoid cystic carcinoma; bladder cancer; bladder carcinoma; carcinoma of the uterus (including endometrial adenocarcinoma, ocular, uterine papillary serous carcinoma, uterine clear-cell carcinoma, uterine sarcomas and leiomyosarcomas, mixed mullerian tumors); glioma, glioblastoma, medulloblastoma, and other tumors of the brain; kidney cancers (including renal cell carcinoma, clear cell carcinoma, Wilm's tumor); cancer of the head and neck (including squamous cell carcinomas); cancer of the stomach (gastric cancers, stomach adenocarcinoma, gastrointestinal stromal tumor); testicular cancer; germ cell tumor; neuroendocrine tumor; cervical cancer; carcinoids of the gastrointestinal tract, breast, and other organs; signet ring cell carcinoma; mesenchymal tumors including sarcomas, fibrosarcomas, haemangioma, angiomatosis, haemangiopericytoma, pseudoangiomatous stromal hyperplasia, myofibroblastoma, fibromatosis, inflammatory myofibroblastic tumor, lipoma, angiolipoma, granular cell tumor, neurofibroma, schwannoma, angiosarcoma, liposarcoma, rhabdomyosarcoma, osteosarcoma, leiomyoma, leiomysarcoma, skin, including melanoma, cervical, retinoblastoma, head and neck cancer, pancreatic, brain, thyroid, testicular, renal, bladder, soft tissue, adenal gland, urethra, cancers of the penis, myxosarcoma, chondrosarcoma, osteosarcoma, chordoma, malignant fibrous histiocytoma, lymphangiosarcoma, mesothelioma, squamous cell carcinoma; epidermoid carcinoma, malignant skin adnexal tumors, adenocarcinoma, hepatoma, hepatocellular carcinoma, renal cell carcinoma, hypernephroma, cholangiocarcinoma, transitional cell carcinoma, choriocarcinoma, seminoma, embryonal cell carcinoma, glioma anaplastic; glioblastoma multiforme, neuroblastoma, medulloblastoma, malignant meningioma, malignant schwannoma, neurofibrosarcoma, parathyroid carcinoma, medullary carcinoma of thyroid, bronchial carcinoid, pheochromocytoma, Islet cell carcinoma, malignant carcinoid, malignant paraganglioma, melanoma, Merkel cell neoplasm, cystosarcoma phylloide, salivary cancers, thymic carcinomas, and cancers of the vagina among others.

[0195] In one embodiment, the methods described herein are useful for treating a host suffering from a lymphoma or lymphocytic or myelocytic proliferation disorder or abnormality. For example, the subject suffering from a Hodgkin Lymphoma of a Non-Hodgkin Lymphoma. For example, the subject can be suffering from a Non-Hodgkin Lymphoma such as, but not limited to: an AIDS-Related Lymphoma; Anaplastic Large-Cell Lymphoma; Angioimmunoblastic Lymphoma; Blastic NK-Cell Lymphoma; Burkitt's Lymphoma; Burkitt-like Lymphoma (Small Non-Cleaved Cell Lymphoma); Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma; Cutaneous T-Cell Lymphoma; Diffuse Large B-Cell Lymphoma; Enteropathy-Type T-Cell Lymphoma; Follicular Lymphoma; Hepatosplenic Gamma-Delta T-Cell Lymphoma; Lymphoblastic Lymphoma; Mantle Cell Lymphoma; Marginal Zone Lymphoma; Nasal T-Cell Lymphoma; Pediatric Lymphoma; Peripheral T-Cell Lymphomas; Primary Central Nervous System Lymphoma; T-Cell Leukemias; Transformed Lymphomas; Treatment-Related T-Cell Lymphomas; or Waldenstrom's Macroglobulinemia.

[0196] Alternatively, the subject may be suffering from a Hodgkin Lymphoma, such as, but not limited to: Nodular Sclerosis Classical Hodgkin's Lymphoma (CHL); Mixed Cellularity CHL; Lymphocyte-depletion CHL; Lymphocyte-rich CHL; Lymphocyte Predominant Hodgkin Lymphoma; or Nodular Lymphocyte Predominant HL.

[0197] In one embodiment, the subject may be suffering from a specific T-cell, a B-cell, or a NK-cell based lymphoma, proliferative disorder, or abnormality. For example, the subject can be suffering from a specific T-cell or NK-cell lymphoma, for example, but not limited to: Peripheral T-cell lymphoma, for example, peripheral T-cell lymphoma and peripheral T-cell lymphoma not otherwise specified (PTCL-NOS); anaplastic large cell lymphoma, for example anaplastic lymphoma kinase (ALK) positive, ALK negative anaplastic large cell lymphoma, or primary cutaneous anaplastic large cell lymphoma; angioimmunoblastic lymphoma; cutaneous T-cell lymphoma, for example mycosis fungoides, Sezary syndrome, primary cutaneous anaplastic large cell lymphoma, primary cutaneous CD30+ T-cell lymphoproliferative disorder; primary cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma; primary cutaneous gamma-delta T-cell lymphoma; primary cutaneous small/medium CD4+ T-cell lymphoma. and lymphomatoid papulosis; Adult T-cell Leukemia/Lymphoma (ATLL); Blastic NK-cell Lymphoma; Enteropathy-type T-cell lymphoma; Hematosplenic gamma-delta T-cell Lymphoma; Lymphoblastic Lymphoma; Nasal NK/T-cell Lymphomas; Treatment-related T-cell lymphomas; for example lymphomas that appear after solid organ or bone marrow transplantation; T-cell prolymphocytic leukemia; T-cell large granular lymphocytic leukemia; Chronic lymphoproliferative disorder of NK-cells; Aggressive NK cell leukemia; Systemic EBV+ T-cell lymphoproliferative disease of childhood (associated with chronic active EBV infection); Hydroa vacciniforme-like lymphoma; Adult T-cell leukemia/lymphoma; Enteropathy-associated T-cell lymphoma; Hepatosplenic T-cell lymphoma; or Subcutaneous panniculitis-like T-cell lymphoma.

[0198] Alternatively, the subject may be suffering from a specific B-cell lymphoma or proliferative disorder such as, but not limited to: multiple myeloma; Diffuse large B cell lymphoma; Follicular lymphoma; Mucosa-Associated Lymphatic Tissue lymphoma (MALT); Small cell lymphocytic lymphoma; Mantle cell lymphoma (MCL); Burkitt lymphoma; Mediastinal large B cell lymphoma; Waldenstrom macroglobulinemia; Nodal marginal zone B cell lymphoma (NMZL); Splenic marginal zone lymphoma (SMZL); Intravascular large B-cell lymphoma; Primary effusion lymphoma; or Lymphomatoid granulomatosis; Chronic lymphocytic leukemia/small lymphocytic lymphoma; B-cell prolymphocytic leukemia; Hairy cell leukemia; Splenic lymphoma/leukemia, unclassifiable; Splenic diffuse red pulp small B-cell lymphoma; Hairy cell leukemia-variant; Lymphoplasmacytic lymphoma; Heavy chain diseases, for example, Alpha heavy chain disease, Gamma heavy chain disease, Mu heavy chain disease; Plasma cell myeloma; Solitary plasmacytoma of bone; Extraosseous plasmacytoma; Primary cutaneous follicle center lymphoma; T cell/histiocyte rich large B-cell lymphoma; DLBCL associated with chronic inflammation; Epstein-Barr virus (EBV)+DLBCL of the elderly; Primary mediastinal (thymic) large B-cell lymphoma; Primary cutaneous DLBCL, leg type; ALK+ large B-cell lymphoma; Plasmablastic lymphoma; Large B-cell lymphoma arising in HHV8-associated multicentric; Castleman disease; B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma; B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma; Nodular sclerosis classical Hodgkin lymphoma; Lymphocyte-rich classical Hodgkin lymphoma; Mixed cellularity classical Hodgkin lymphoma; or Lymphocyte-depleted classical Hodgkin lymphoma.

[0199] In one embodiment, the subject is suffering from a leukemia. For example, the subject may be suffering from an acute or chronic leukemia of a lymphocytic or myelogenous origin, such as, but not limited to: Acute lymphoblastic leukemia (ALL); Acute myelogenous leukemia (AML); Chronic lymphocytic leukemia (CLL); Chronic myelogenous leukemia (CML); juvenile myelomonocytic leukemia (JMML); hairy cell leukemia (HCL); acute promyelocytic leukemia (a subtype of AML); T-cell prolymphocytic leukemia (TPLL); large granular lymphocytic leukemia; or Adult T-cell chronic leukemia; large granular lymphocytic leukemia (LGL). In one embodiment, the patient suffers from an acute myelogenous leukemia, for example an undifferentiated AML (M0); myeloblastic leukemia (M1; with/without minimal cell maturation); myeloblastic leukemia (M2; with cell maturation); promyelocytic leukemia (M3 or M3 variant [M3V]); myelomonocytic leukemia (M4 or M4 variant with eosinophilia [M4E]); monocytic leukemia (M5); erythroleukemia (M6); or megakaryoblastic leukemia (M7).

[0200] In a particular embodiment, the subject is suffering, or suspected to be suffering from, a breast cancer, lung cancer, a colon cancer, pancreatic cancer, or brain cancer. In a particular embodiment, the subject is suffering from, or suspected to be suffering from, a breast cancer.

[0201] The sample(s) to be used in accordance with the present invention can be an extracted sample, that is, a sample that has been extracted from the subject. Examples of the sample include, but are not limited to, a tissue, cells, blood and/or a body fluid of a subject. It can be, e.g., a sample obtained from a cancer lesion, or from a lesion suspected for cancer, or from a metastatic tumor, or from a body cavity in which fluid is present which is contaminated with cancer cells (e.g., pleural or abdominal cavity or bladder cavity), or from other body fluids containing cancer cells, and so forth, for example, via a biopsy procedure or other sample extraction procedure. The cells of which a sample is extracted may also be tumorous cells from hematologic malignancies (such as leukemia or lymphoma). In some cases, the cell sample may also be circulating tumor cells, that is, tumor cells that have entered the bloodstream and may be extracted using suitable isolation techniques, e.g., apheresis or conventional venous blood withdrawal. Aside from blood, a body fluid of which a sample is extracted may be urine, gastrointestinal contents, or anextravasate.

[0202] In one aspect of the present invention, the methods and apparatuses described herein are used to identify an active TGF-.beta. cellular signaling pathway in a subject suffering from a cancer, and administering to the subject an anti-cancer agent, for example a TGF-.beta. inhibitor, selected from, but not limited to, Terameprocol, Fresolimumab, Sotatercept, Galunisertib, SB431542, LY2109761, LDN-193189, SB525334, SB505124, GW788388, LY364947, RepSox, LDN-193189 HCl, K02288, LDN-214117, SD-208, EW-7197, ML347, LDN-212854, DMH1, Pirfenidone, Hesperetin, Trabedersen, Lerdelimumab, Metelimumab, trx-SARA, ID11, Ki26894, or SB-431542. Another aspect of the present invention relates to a method (as described herein), further comprising:

[0203] determining whether the TGF-.beta. cellular signaling pathway is operating abnormally in the subject based on the calculated activity of the TGF-.beta. cellular signaling pathway in the subject.

[0204] Here, the term "abnormally" denotes disease-promoting activity of the TGF-.beta. cellular signaling pathway, for example, a tumor-promoting activity.

[0205] The present invention also relates to a method (as described herein) further comprising:

[0206] recommending prescribing a drug, for example a TGF-.beta. inhibitor, for the subject that corrects for abnormal operation of the TGF-.beta. cellular signaling pathway,

[0207] wherein the recommending is performed if the TGF-.beta. cellular signaling pathway is determined to be operating abnormally in the subject based on the calculated/determined activity of the TGF-.beta. cellular signaling pathway.

[0208] The present invention also relates to a method (as described herein), wherein the calculating/determining comprises:

[0209] calculating the activity of the TGF-.beta. cellular signaling pathway in the subject based at least on expression levels of two, three or more target genes of a set of target genes of the TGF-.beta. cellular signaling pathway measured in the sample of the subject.

[0210] In one embodiment,

[0211] the set of target genes of the TGF-.beta. cellular signaling pathway includes at least seven, or in an alternative, all target genes selected from the group consisting of: ANGPTL4, CDC42EP3, CDKN1A, CDKN2B, CTGF, GADD45A, GADD45B, HMGA2, ID1, IL11, INPP5D, JUNB, MMP2, MMP9, NKX2-5, OVOL1, PDGFB, PTHLH, SGK1, SKIL, SMAD4, SMAD5, SMAD6, SMAD7, SNAIL SNAI2, TIMP1, and VEGFA, or from the group consisting of: ANGPTL4, CDC42EP3, CDKN1A, CTGF, GADD45A, GADD45B, HMGA2, ID1, IL11, JUNB, PDGFB, PTHLH, SGK1, SKIL, SMAD4, SMAD5, SMAD6, SMAD7, SNAI2, and VEGFA, or from the group consisting of: ANGPTL4, CDC42EP3, CDKN1A, CTGF, GADD45B, ID1, IL11, JUNB, PDGFB, SKIL, SMAD7, and SNAI2, or from the group consisting of: ANGPTL4, CDC42EP3, ID1, IL11, JUNB, SKIL, and SMAD7.

[0212] The present invention as described herein can, e.g., also advantageously be used in connection with:

[0213] diagnosis based on the determined activity of the TGF-.beta. cellular signaling pathway in the subject;

[0214] prognosis based on the determined activity of the TGF-.beta. cellular signaling pathway in the subject;

[0215] drug prescription based on the determined activity of the TGF-.beta. cellular signaling pathway in the subject;

[0216] prediction of drug efficacy based on the determined activity of the TGF-.beta. cellular signaling pathway in the subject;

[0217] prediction of adverse effects based on the determined activity of the TGF-.beta. cellular signaling pathway in the subject;

[0218] monitoring of drug efficacy;

[0219] drug development;

[0220] assay development;

[0221] pathway research;

[0222] cancer staging;

[0223] enrollment of the subject in a clinical trial based on the determined activity of the TGF-.beta. cellular signaling pathway in the subject;

[0224] selection of subsequent test to be performed; and

[0225] selection of companion diagnostics tests.

[0226] Further advantages will be apparent to those of ordinary skill in the art upon reading and understanding the attached figures, the following description and, in particular, upon reading the detailed examples provided herein below.

[0227] It shall be understood that an embodiment of the present invention can also be any combination of the dependent claims or above embodiments with the respective independent claim.

[0228] These and other aspects of the invention will be apparent from and elucidated with reference to the embodiments described hereinafter.

EXAMPLES

[0229] The following examples merely illustrate exemplary methods and selected aspects in connection therewith. The teaching provided therein may be used for constructing several tests and/or kits, e.g., to detect, predict and/or diagnose the abnormal activity of the TGF-B cellular signaling pathways. Furthermore, upon using methods as described herein drug prescription can advantageously be guided, drug response prediction and monitoring of drug efficacy (and/or adverse effects) can be made, drug resistance can be predicted and monitored, e.g., to select subsequent test(s) to be performed (like a companion diagnostic test). The following examples are not to be construed as limiting the scope of the present invention.

Example 1

Mathematical Model Construction

[0230] As described in detail in the published international patent application WO 2013/011479 A2 ("Assessment of cellular signaling pathway activity using probabilistic modeling of target gene expression"), by constructing a probabilistic model, e.g., a Bayesian network model, and incorporating conditional probabilistic relationships between expression levels of one or more target gene(s) of a cellular signaling pathway, herein, the TGF-.beta. cellular signaling pathway, and the level of a transcription factor (TF) element, herein, the TGF-.beta. TF element, the TF element controlling transcription of the one or more target gene(s) of the cellular signaling pathway, such a model may be used to determine the activity of the cellular signaling pathway with a high degree of accuracy. Moreover, the probabilistic model can be readily updated to incorporate additional knowledge obtained by later clinical studies, by adjusting the conditional probabilities and/or adding new nodes to the model to represent additional information sources. In this way, the probabilistic model can be updated as appropriate to embody the most recent medical knowledge.

[0231] In another easy to comprehend and interpret approach described in detail in the published international patent application WO 2014/102668 A2 ("Assessment of cellular signaling pathway activity using linear combination(s) of target gene expressions"), the activity of a cellular signaling pathway, herein, the TGF-.beta. cellular signaling pathway, may be determined by constructing and evaluating a linear or (pseudo-)linear model incorporating relationships between expression levels of one or more target gene(s) of the cellular signaling pathway and the level of a transcription factor (TF) element, herein, the TGF-.beta. TF element, the TF element controlling transcription of the one or more target gene(s) of the cellular signaling pathway, the model being based at least in part on one or more linear combination(s) of expression levels of the one or more target gene(s).

[0232] In both approaches, the expression levels of the one or more target gene(s) may, for example, be measurements of the level of mRNA, which can be the result of, e.g., (RT)-PCR and microarray techniques using probes associated with the target gene(s) mRNA sequences, and of RNA-sequencing. In another embodiment, the expression levels of the one or more target gene(s) can be measured by protein levels, e.g., the concentrations and/or activity of the protein(s) encoded by the target gene(s).

[0233] The aforementioned expression levels may optionally be converted in many ways that might or might not suit the application better. For example, four different transformations of the expression levels, e.g., microarray-based mRNA levels, may be: [0234] "continuous data", i.e., expression levels as obtained after preprocessing of microarrays using well known algorithms such as MAS5.0 and fRMA, [0235] "z-score", i.e., continuous expression levels scaled such that the average across all samples is 0 and the standard deviation is 1, [0236] "discrete", i.e., every expression above a certain threshold is set to 1 and below it to 0 (e.g., the threshold for a probeset may be chosen as the (weighted) median of its value in a set of a number of positive and the same number of negative clinical samples), [0237] "fuzzy", i.e., the continuous expression levels are converted to values between 0 and 1 using a sigmoid function of the following format: 1/(1+exp((thr-expr)/se)), with expr being the continuous expression levels, thr being the threshold as mentioned before and se being a softening parameter influencing the difference between 0 and 1.

[0238] One of the simplest linear models that can be constructed is a model having a node representing the transcription factor (TF) element, herein, the TGF-.beta. TF element, in a first layer and weighted nodes representing direct measurements of the target gene(s) expression levels, e.g., by one probeset that is particularly highly correlated with the particular target gene, e.g., in microarray or (q)PCR experiments, in a second layer. The weights can be based either on calculations from a training data set or based on expert knowledge. This approach of using, in the case where possibly multiple expression levels are measured per target gene (e.g., in the case of microarray experiments, where one target gene can be measured with multiple probesets), only one expression level per target gene is particularly simple. A specific way of selecting the one expression level that is used for a particular target gene is to use the expression level from the probeset that is able to separate active and passive samples of a training data set the best. One method to determine this probeset is to perform a statistical test, e.g., the t-test, and select the probeset with the lowest p-value. The training data set's expression levels of the probeset with the lowest p-value is by definition the probeset with the least likely probability that the expression levels of the (known) active and passive samples overlap. Another selection method is based on odds-ratios. In such a model, one or more expression level(s) are provided for each of the one or more target gene(s) and the one or more linear combination(s) comprise a linear combination including for each of the one or more target gene(s) a weighted term, each weighted term being based on only one expression level of the one or more expression level(s) provided for the respective target gene. If the only one expression level is chosen per target gene as described above, the model may be called a "most discriminant probesets" model.

[0239] In an alternative to the "most discriminant probesets" model, it is possible, in the case where possibly multiple expression levels are measured per target gene, to make use of all the expression levels that are provided per target gene. In such a model, one or more expression level(s) are provided for each of the one or more target gene(s) and the one or more linear combination(s) comprise a linear combination of all expression levels of the one or more expression level(s) provided for the one or more target gene(s). In other words, for each of the one or more target gene(s), each of the one or more expression level(s) provided for the respective target gene may be weighted in the linear combination by its own (individual) weight. This variant may be called an "all probesets" model. It has an advantage of being relatively simple while making use of all the provided expression levels.

[0240] Both models as described above have in common that they are what may be regarded as "single-layer" models, in which the level of the TF element is calculated based on a linear combination of expression levels of the one or more probeset of the one or more target genes.

[0241] After the level of the TF element, herein, the TGF-.beta. TF element, has been determined by evaluating the respective model, the determined TF element level can be thresholded in order to infer the activity of the cellular signaling pathway, herein, the TGF-.beta. cellular signaling pathway. An exemplary method to calculate such an appropriate threshold is by comparing the determined TF element levels wlc of training samples known to have a passive cellular signaling pathway and training samples with an active cellular signaling pathway. A method that does so and also takes into account the variance in these groups is given by using a threshold

thr = .sigma. wlc pas .mu. wlc act + .sigma. wlc act .mu. wlc pas .sigma. wlc pas + .sigma. wlc act ( 1 ) ##EQU00001##

where .sigma. and .mu. are the standard deviation and the mean of the determined TF element levels wlc for the training samples. In case only a small number of samples are available in the active and/or passive training samples, a pseudocount may be added to the calculated variances based on the average of the variances of the two groups:

v ~ = v wlc act + v wlc pas 2 v ~ wlc act = x v ~ + ( n act - 1 ) v wlc act x + n act - 1 v ~ wlc pas = x v ~ + ( n pas - 1 ) v wlc pas x + n pas - 1 ( 2 ) ##EQU00002##

where v is the variance of the determined TF element levels wlc of the groups, x is a positive pseudocount, e.g., 1 or 10, and nact and npas are the number of active and passive samples, respectively. The standard deviation .sigma. can next be obtained by taking the square root of the variance v.

[0242] The threshold can be subtracted from the determined TF element levels wlc for ease of interpretation, resulting in a cellular signaling pathway's activity score in which negative values correspond to a passive cellular signaling pathway and positive values correspond to an active cellular signaling pathway.

[0243] As an alternative to the above-described "single-layer" models, a "two-layer" may also be used in an example. In such a model, a summary value is calculated for every target gene using a linear combination based on the measured intensities of its associated probesets ("first (bottom) layer"). The calculated summary value is subsequently combined with the summary values of the other target genes of the cellular signaling pathway using a further linear combination ("second (upper) layer"). Again, the weights can be either learned from a training data set or based on expert knowledge or a combination thereof. Phrased differently, in the "two-layer" model, one or more expression level(s) are provided for each of the one or more target gene(s) and the one or more linear combination(s) comprise for each of the one or more target gene(s) a first linear combination of all expression levels of the one or more expression level(s) provided for the respective target gene ("first (bottom) layer"). The model is further based at least in part on a further linear combination including for each of the one or more target gene(s) a weighted term, each weighted term being based on the first linear combination for the respective target gene ("second (upper) layer").

[0244] The calculation of the summary values can, in an exemplary version of the "two-layer" model, include defining a threshold for each target gene using the training data and subtracting the threshold from the calculated linear combination, yielding the target gene summary. Here the threshold may be chosen such that a negative target gene summary value corresponds to a down-regulated target gene and that a positive target gene summary value corresponds to an up-regulated target gene. Also, it is possible that the target gene summary values are transformed using, e.g., one of the above-described transformations (fuzzy, discrete, etc.), before they are combined in the "second (upper) layer".

[0245] After the level of the TF element has been determined by evaluating the "two-layer" model, the determined TF element level can be thresholded in order to infer the activity of the cellular signaling pathway, as described above.

[0246] In the following, the models described above are collectively denoted as "(pseudo-)linear" models. A more detailed description of the training and use of probabilistic models, e.g., a Bayesian network model, is provided in Example 3 below.

Example 2

Selection of Target Genes

[0247] A transcription factor (TF) is a protein complex (i.e., a combination of proteins bound together in a specific structure) or a protein that is able to regulate transcription from target genes by binding to specific DNA sequences, thereby controlling the transcription of genetic information from DNA to mRNA. The mRNA directly produced due to this action of the TF complex is herein referred to as a "direct target gene" (of the transcription factor). Cellular signaling pathway activation may also result in more secondary gene transcription, referred to as "indirect target genes". In the following, (pseudo-)linear models or Bayesian network models (as exemplary mathematical models) comprising or consisting of direct target genes as direct links between cellular signaling pathway activity and mRNA level, are exemplified, however the distinction between direct and indirect target genes is not always evident. Herein, a method to select direct target genes using a scoring function based on available scientific literature data is presented. Nonetheless, an accidental selection of indirect target genes cannot be ruled out due to limited information as well as biological variations and uncertainties. In order to select the target genes, the MEDLINE database of the National Institute of Health accessible at "www.ncbi.nlm.nih.gov/pubmed" and herein further referred to as "Pubmed" was employed to generate a lists of target genes. Furthermore, three additional lists of target genes were selected based on the probative nature of their expression.

[0248] Publications containing putative TGF-.beta. target genes were searched for by using queries such as ("TGF-.beta." AND "target gene") in the period of fourth quarter of 2013 and the first quarter of 2014. The resulting publications were further analyzed manually following the methodology described in more detail below.

[0249] Specific cellular signaling pathway mRNA target genes were selected from the scientific literature, by using a ranking system in which scientific evidence for a specific target gene was given a rating, depending on the type of scientific experiments in which the evidence was accumulated. While some experimental evidence is merely suggestive of a gene being a direct target gene, like for example an mRNA increasing as detected by means of an increasing intensity of a probeset on a microarray of a cell line in which it is known that the TGF-.beta. cellular signaling pathway is active, other evidence can be very strong, like the combination of an identified TGF-.beta. cellular signaling pathway TF binding site and retrieval of this site in a chromatin immunoprecipitation (ChIP) assay after stimulation of the specific cellular signaling pathway in the cell and increase in mRNA after specific stimulation of the cellular signaling pathway in a cell line.

[0250] Several types of experiments to find specific cellular signaling pathway target genes can be identified in the scientific literature: [0251] 1. ChIP experiments in which direct binding of a TF of the cellular signaling pathway of interest to its binding site on the genome is shown. Example: By using chromatin immunoprecipitation (ChIP) technology subsequently putative functional TGF-.beta. TF binding sites in the DNA of cell lines with and without active induction of the TGF-.beta. cellular signaling pathway, e.g., by stimulation with TGF-.beta., were identified, as a subset of the binding sites recognized purely based on nucleotide sequence. Putative functionality was identified as ChIP-derived evidence that the TF was found to bind to the DNA binding site. [0252] 2. Electrophoretic Mobility Shift (EMSA) assays which show in vitro binding of a TF to a fragment of DNA containing the binding sequence. Compared to ChIP-based evidence EMSA-based evidence is less strong, since it cannot be translated to the in vivo situation. [0253] 3. Stimulation of the cellular signaling pathway and measuring mRNA expression using a microarray, RNA sequencing, quantitative PCR or other techniques, using TGF-.beta. cellular signaling pathway-inducible cell lines and measuring mRNA profiles measured at least one, but may be, in an alternative, several time points after induction--in the presence of cycloheximide, which inhibits translation to protein, thus the induced mRNAs are assumed to be direct target genes. [0254] 4. Similar to 3, but alternatively measure the mRNAs expression further downstream with protein abundance measurements, such as western blot. [0255] 5. Identification of TF binding sites in the genome using a bioinformatics approach. Example for the TGF-.beta. TF element: Using the SMAD binding motif 5'-AGAC-3', a software program was run on the human genome sequence, and potential binding sites were identified, both in gene promoter regions and in other genomic regions. [0256] 6. Similar as 3, only in the absence of cycloheximide. [0257] 7. Similar to 4, only in the absence of cycloheximide.

[0258] In the simplest form one can give every potential gene 1 point for each of these experimental approaches in which the gene was identified as being a target gene of the TGF-.beta. family of transcription factors. Using this relative ranking strategy, one can make a list of most reliable target genes.

[0259] Alternatively, ranking in another way can be used to identify the target genes that are most likely to be direct target genes, by giving a higher number of points to the technology that provides most evidence for an in vivo direct target gene. In the list above, this would mean 8 points for experimental approach 1), 7 for 2), and going down to 1 point for experimental approach 8). Such a list may be called a "general list of target genes".

[0260] Despite the biological variations and uncertainties, the inventors assumed that the direct target genes are the most likely to be induced in a tissue-independent manner. A list of these target genes may be called an "evidence curated list of target genes". Such an evidence curated list of target genes has been used to construct computational models of the TGF-.beta. cellular signaling pathway that can be applied to samples coming from different tissue sources.

[0261] The following will illustrate exemplary how the selection of an evidence curated target gene list specifically was constructed for the TGF-.beta. cellular signaling pathway.

[0262] A scoring function was introduced that gave a point for each type of experimental evidence, such as ChIP, EMSA, differential expression, knock down/out, luciferase gene reporter assay, sequence analysis, that was reported in a publication. The same experimental evidence is sometimes mentioned in multiple publications resulting in a corresponding number of points, e.g., two publications mentioning a ChIP finding results in twice the score that is given for a single ChIP finding. Further analysis was performed to allow only for genes that had diverse types of experimental evidence and not only one type of experimental evidence, e.g., differential expression. Those genes that had more than one type of experimental evidence available were selected (as shown in Table 4).

[0263] A further selection of the evidence curated list of target genes (listed in Table 5) was made by the inventors. The target genes of the evidence curated list that were proven to be more probative in determining the activity of the TGF-.beta. signaling pathway from the training samples were selected. Herein, samples from GSE17708 stimulated with 5 ng/mL TGF-.beta. for 4 hours were chosen as active or tumor promoting TGF-.beta. activity whereas the unstimulated samples were chosen as the passive or tumor suppressing TGF-.beta. samples for training, alternatively, one can use patient samples of primary cells or other cell lines stimulated with and deprived of TGF-.beta., e.g. GSE6653, GSE42373 and GSE18670. All target genes that had a "soft" odds ratio (see below) between active and passive training samples of more than 2 or less than 0.5 for negatively regulated target genes were selected for the "20 target genes shortlist". Target genes that were found to have a "soft" odds ratio of more than 10 or less than 0.1 are selected for the "12 target genes shortlist". The "7 target genes shortlist" consists of target genes that were found to have a "soft" odds ratio of more than 15 or less than 1/15. The 20 target genes shortlist, the 12 target genes shortlist, and the 7 target genes shortlist are shown in Tables 5 to 7, respectively.

TABLE-US-00004 TABLE 4 "Evidence curated list of target genes" of the TGF-.beta. cellular signaling pathway used in the TGF-.beta. cellular signaling pathway models and associated probesets used to measure the mRNA expression level of the target genes. Target gene Probeset ANGPTL4 223333_s_at 221009_s_at CDC42EP3 209286_a 209288_s_at 225685_at 209287_s_at CDKN1A 202284_s_at 1555186_at CDKN2B 236313_at 207530_s_at CTGF 209101_at GADD45A 203725_at GADD45B 207574_s_at 209305_s_at 209304_x_at HMGA2 208025_s_at 1567224_at 1568287_at 1558683_a_at 1561633_at 1559891_at 1558682_at ID1 208937_s_at IL11 206924_at 206926_s_at INPP5D 203331_s_at 1568943_at 203332_s_at JUNB 201473_at MMP2 1566678_at 201069_at MMP9 203936_s_at NKX2-5 206578_at OVOL1 206604_at 229396_at PDGFB 204200_s_at 216061_x_at 217112_at 217430_x_at PTHLH 210355_at 206300_s_at 1556773_at 211756_at SGK1 201739_at SKIL 206675_s_at 225227_at 215889_at SMAD4 202526_at 202527_s_at 1565703_at 235725_at SMAD5 225223_at 235451_at 225219_at 205187_at 205188_s_at SMAD6 207069_s_at 209886_s_at SMAD7 204790_at SNAI1 219480_at SNAI2 213139_at TIMP1 201666_at VEGFA 210513_s_at 210512_s_at 212171_x_at 211527_x_at

TABLE-US-00005 TABLE 5 "20 target genes shortlist" of target genes of the TGF-.beta. cellular signaling pathway based on the evidence curated list of target genes. ANGPTL4 CDC42EP3 CDKN1A CTGF GADD45A GADD45B HMGA2 ID1 IL11 JUNB PDGFB PTHLH SGK1 SKIL SMAD4 SMAD5 SMAD6 SMAD7 SNAI2 VEGFA

TABLE-US-00006 TABLE 6 "12 target genes shortlist" of target genes of the TGF-.beta. cellular signaling pathway based on the evidence curated list of target genes. ANGPTL4 CDC42EP3 CDKN1A CTGF GADD45B ID1 IL11 JUNB PDGFB SKIL SMAD7 SNAI2

TABLE-US-00007 TABLE 7 "7 target genes shortlist" of target genes of the TGF-.beta. cellular signaling pathway based on the evidence curated list of target genes. ANGPTL4 CDC42EP3 ID1 IL11 JUNB SKIL SMAD7

Example 3

Training and Using the Mathematical Model

[0264] Before the mathematical model can be used to infer the activity of the cellular signaling pathway, herein, the TGF-.beta. cellular signaling pathway, in a subject, the model must be appropriately trained.

[0265] If the mathematical model is a probabilistic model, e.g., a Bayesian network model, based at least in part on conditional probabilities relating the TGF-.beta. TF element and expression levels of the one or more target gene(s) of the TGF-.beta. cellular signaling pathway measured in the sample of the subject, the training may, for example, be performed as described in detail in the published international patent application WO 2013/011479 A2 ("Assessment of cellular signaling pathway activity using probabilistic modeling of target gene expression").

[0266] If the mathematical model is based at least in part on one or more linear combination(s) of expression levels of the one or more target gene(s) of the TGF-.beta. cellular signaling pathway measured in the sample of the subject, the training may, for example, be performed as described in detail in the published international patent application WO 2014/102668 A2 ("Assessment of cellular signaling pathway activity using linear combination(s) of target gene expressions").

[0267] Herein, an exemplary Bayesian network model as shown in FIG. 2 was used to model the transcriptional program of the TGF-.beta. cellular signaling pathway in a simple manner. The model consists of three types of nodes: (a) a transcription factor (TF) element (with states "absent" and "present") in a first layer 1; (b) target gene(s) TG1, TG2, TGn (with states "down" and "up") in a second layer 2, and; (c) measurement nodes linked to the expression levels of the target gene(s) in a third layer 3. These can be microarray probesets PS1,1, PS1,2, PS1,3, PS2,1, PSn,1, PS n,m (with states "low" and "high"), as exemplified herein, but could also be other gene expression measurements such as RNAseq or RT-qPCR.

[0268] A suitable implementation of the mathematical model, herein, the exemplary Bayesian network model, is based on microarray data. The model describes (i) how the expression levels of the target gene(s) depend on the activation of the TF element, and (ii) how probeset intensities, in turn, depend on the expression levels of the respective target gene(s). For the latter, probeset intensities may be taken from fRMA pre-processed Affymetrix HG-U133Plus2.0 microarrays, which are widely available from the Gene Expression Omnibus (GEO, www.ncbi.nlm.nih.gov/geo) and ArrayExpress (www. ebi.ac.uk/arrayexpress).

[0269] As the exemplary Bayesian network model is a simplification of the biology of a cellular signaling pathway, herein, the TGF-.beta. cellular signaling pathway, and as biological measurements are typically noisy, a probabilistic approach was opted for, i.e., the relationships between (i) the TF element and the target gene(s), and (ii) the target gene(s) and their respective probesets, are described in probabilistic terms. Furthermore, it was assumed that the activity of the oncogenic cellular signaling pathway which drives tumor growth is not transiently and dynamically altered, but long term or even irreversibly altered. Therefore the exemplary Bayesian network model was developed for interpretation of a static cellular condition. For this reason complex dynamic cellular signaling pathway features were not incorporated into the model.

[0270] Once the exemplary Bayesian network model is built and calibrated (see below), the model can be used on microarray data of a new sample by entering the probeset measurements as observations in the third layer 3, and mathematically inferring backwards in the model what the probability must have been for the TF element to be "present". Here, "present" is considered to be the phenomenon that the TF element is bound to the DNA and is controlling transcription of the cellular signaling pathway's target genes, and "absent" the case that the TF element is not controlling transcription. This probability is hence the primary read-out that may be used to indicate activity of the cellular signaling pathway, herein, the TGF-.beta. cellular signaling pathway, which can next be translated into the odds of the cellular signaling pathway being active by taking the ratio of the probability of it being active vs. it being passive (i.e., the odds are given by p/(1-p), where p is the predicted probability of the cellular signaling pathway being active).

[0271] In the exemplary Bayesian network model, the probabilistic relations have been made quantitative to allow for a quantitative probabilistic reasoning. In order to improve the generalization behavior across tissue types, the parameters describing the probabilistic relationships between (i) the TF element and the target gene(s) have been carefully hand-picked. If the TF element is "absent", it is most likely that the target gene is "down", hence a probability of 0.95 is chosen for this, and a probability of 0.05 is chosen for the target gene being "up". The latter (non-zero) probability is to account for the (rare) possibility that the target gene is regulated by other factors or that it is accidentally observed as being "up" (e.g. because of measurement noise). If the TF element is "present", then with a probability of 0.70 the target gene is considered "up", and with a probability of 0.30 the target gene is considered "down". The latter values are chosen this way, because there can be several causes why a target gene is not highly expressed even though the TF element is present, e.g., because the gene's promoter region is methylated. In the case that a target gene is not up-regulated by the TF element, but down-regulated, the probabilities are chosen in a similar way, but reflecting the down-regulation upon presence of the TF element. The parameters describing the relationships between (ii) the target gene(s) and their respective probesets have been calibrated on experimental data. For the latter, in this example, microarray data was used from patients samples which are known to have an active TGF-.beta. cellular signaling pathway whereas normal, healthy samples from the same dataset were used as passive TGF-.beta. cellular signaling pathway samples, but this could also be performed using cell line experiments or other patient samples with known cellular signaling pathway activity status. The resulting conditional probability tables are given by: [0272] A: for upregulated target genes

TABLE-US-00008 [0272] PSi, j = low PSi, j = high TGi = down AL i , j + 1 AL i , j + AH i , j + 2 ##EQU00003## AH i , j + 1 AL i , j + AH i , j + 2 ##EQU00004## TGi = up PL i , j + 1 PL i , j + PH i , j + 2 ##EQU00005## PH i , j + 1 PL i , j + PH i , j + 2 ##EQU00006##

[0273] B: for downregulated target genes

TABLE-US-00009 [0273] PSi, j = low PSi, j = high TGi = down PL i , j + 1 PL i , j + PH i , j + 2 ##EQU00007## PH i , j + 1 PL i , j + PH i , j + 2 ##EQU00008## TGi = up AL i , j + 1 AL i , j + AH i , j + 2 ##EQU00009## AH i , j + 1 AL i , j + AH i , j + 2 ##EQU00010##

[0274] In these tables, the variables ALi,j, AHi,j, PLi,j, and PHi,j indicate the number of calibration samples with an "absent" (A) or "present" (P) transcription complex that have a "low" (L) or "high" (H) probeset intensity, respectively. Dummy counts have been added to avoid extreme probabilities of 0 and 1.

[0275] To discretize the observed probeset intensities, for each probeset PSi,j a threshold ti,j was used, below which the observation is called "low", and above which it is called "high". This threshold has been chosen to be the (weighted) median intensity of the probeset in the used calibration dataset. Due to the noisiness of microarray data, a fuzzy method was used when comparing an observed probeset intensity to its threshold, by assuming a normal distribution with a standard deviation of 0.25 (on a log 2 scale) around the reported intensity, and determining the probability mass below and above the threshold.

[0276] If instead of the exemplary Bayesian network described above, a (pseudo-)linear model as described in Example 1 above was employed, the weights indicating the sign and magnitude of the correlation between the nodes and a threshold to call whether a node is either "absent" or "present" would need to be determined before the model could be used to infer cellular signaling pathway activity in a test sample. One could use expert knowledge to fill in the weights and the threshold a priori, but typically the model would be trained using a representative set of training samples, of which, for example, the ground truth is known, e.g., expression data of probesets in samples with a known "present" transcription factor complex (=active cellular signaling pathway) or "absent" transcription factor complex (=passive cellular signaling pathway).

[0277] Known in the field are a multitude of training algorithms (e.g., regression) that take into account the model topology and changes the model parameters, here, the weights and the threshold, such that the model output, here, a weighted linear score, is optimized. Alternatively, it is also possible to calculate the weights directly from the expression observed levels without the need of an optimization algorithm.

[0278] A first method, named "black and white"-method herein, boils down to a ternary system, in which each weight is an element of the set {-1, 0, 1}. If this is put in a biological context, the -1 and 1 correspond to target genes or probesets that are down- and up-regulated in case of cellular signaling pathway activity, respectively. In case a probeset or target gene cannot be statistically proven to be either up- or down-regulated, it receives a weight of 0. In one example, a left-sided and right-sided, two sample t-test of the expression levels of the active cellular signaling pathway samples versus the expression levels of the samples with a passive cellular signaling pathway can be used to determine whether a probe or gene is up- or down-regulated given the used training data. In cases where the average of the active samples is statistically larger than the passive samples, i.e., the p-value is below a certain threshold, e.g., 0.3, the target gene or probeset is determined to be up-regulated. Conversely, in cases where the average of the active samples is statistically lower than the passive samples, the target gene or probeset is determined to be down-regulated upon activation of the cellular signaling pathway. In case the lowest p-value (left- or right-sided) exceeds the aforementioned threshold, the weight of the target gene or probeset can be defined to be 0.

[0279] A second method, named "log odds"-weights herein, is based on the logarithm (e.g., base e) of the odds ratio. The odds ratio for each target gene or probeset is calculated based on the number of positive and negative training samples for which the probeset/target gene level is above and below a corresponding threshold, e.g., the (weighted) median of all training samples. A pseudo-count can be added to circumvent divisions by zero. A further refinement is to count the samples above/below the threshold in a somewhat more probabilistic manner, by assuming that the probeset/target gene levels are e.g. normally distributed around its observed value with a certain specified standard deviation (e.g., 0.25 on a 2-log scale), and counting the probability mass above and below the threshold. Herein, an odds ratio calculated in combination with a pseudo-count and using probability masses instead of deterministic measurement values is called a "soft" odds ratio.

[0280] Further details regarding the determining of cellular signaling pathway activity using mathematical modeling of target gene expression can be found in Verhaegh W. et al., "Selection of personalized patient therapy through the use of knowledge-based computational models that identify tumor-driving signal transduction pathways", Cancer Research, Vol. 74, No. 11, 2014, pages 2936 to 2945.

[0281] Herein, expression data of human A549 lung adenocarcinoma cell line samples that were either treated with 5 ng/mL TGF-.beta., resulting in an tumor promoting activity of the TGF-.beta. cellular signaling pathway (from now on referred to as TGF-.beta. active), and a control experiment without TGF-.beta. stimulation, resulting in a tumor suppressing activity of the TGF-.beta. cellular signaling pathway (from now on referred to as TGF-.beta. passive), was used for calibration. These microarrays are publically available under GSE17708 from the gene expression omnibus (GEO, www.ncbi.nlm.nih.gov/geo/, last accessed Mar. 5, 2014). The samples stimulated with 5 ng/mL TGF-.beta. for 4 hours were chosen as representatives of the active or tumor promoting TGF-.beta. cell lines based on the observed fold change of the selected genes (Table 4) compared to the unstimulated samples that were chosen as the passive or tumor suppressing TGF-.beta. samples for training. Alternatively, one can use patient samples of primary cells or other cell lines stimulated with and deprived of TGF-.beta., e.g. GSE6653, GSE42373 and GSE18670.

[0282] FIGS. 9 to 12 show training results of the exemplary Bayesian network model based on the list of evidence curated target genes, the 20 target genes shortlist, the 12 target genes shortlist and the 7 target genes shortlist of the TGF-.beta. cellular signaling pathway (see Tables 4 to 7), respectively. In the diagrams, the vertical axis indicates the odds that the TF element is "present" resp. "absent", which corresponds to the TGF-.beta. cellular signaling pathway being active resp. passive, wherein values above the horizontal axis correspond to the TF element being more likely "present"/active and values below the horizontal axis indicate that the odds that the TF element is "absent"/passive are larger than the odds that it is "present"/active. The A549 cell line samples that were stimulated with TGF-.beta. for 4 hours (group 5) were used to represent the active or tumor promoting training samples, whereas the unstimulated samples (group 1) were used as a representation of the passive or tumor suppressing TGF-.beta. cellular signaling pathway. The models using the different target gene lists were able to clearly separate the passive from the active training samples. In addition, one can appreciate from the results that all stimulation of 1 hour or longer resulted in the TGF-.beta. cellular signaling pathway having tumor promoting activities for all four target gene lists. Stimulation of 0.5 h with TGF-.beta. resulted in TGF-.beta. activities varying from TGF-.beta. passive to active, which is likely caused by the relatively short TGF-.beta. stimulation. (Legend: 1--Control; 2--TGF-.beta. stimulation with 5 ng/mL for 0.5 h; 3--TGF-.beta. stimulation with 5 ng/mL for 1 h; 4--TGF-.beta. stimulation with 5 ng/mL for 2 h; 5--TGF-.beta. stimulation with 5 ng/mL for 4 h; 6--TGF-.beta. stimulation with 5 ng/mL for 8 h; 7--TGF-.beta. stimulation with 5 ng/mL for 16 h; 8--TGF-.beta. stimulation with 5 ng/mL for 24 h; 9--TGF-.beta. stimulation with 5 ng/mL for 72 h)

[0283] In the following, validation results of the trained exemplary Bayesian network model using the evidence curated list of target genes, the 20 target genes shortlist, the 12 target genes shortlist, and the 7 target genes shortlist, respectively, are shown in FIGS. 13 to 23.

[0284] FIGS. 13 to 16 show TGF-.beta. cellular signaling pathway activity predictions of the trained exemplary Bayesian network models using the evidence curated list of target genes, the 20 target genes shortlist, the 12 target genes shortlist, and the 7 target genes shortlist (see Tables 4 to 7), respectively, for human mammary epithelial cells (HMEC-TR) from GSE28448. In the diagrams, the vertical axis indicates the odds that the TF element is "present" resp. "absent", which corresponds to the TGF-.beta. cellular signaling pathway being active resp. passive, wherein values above the horizontal axis correspond to the TF element being more likely "present"/active and values below the horizontal axis indicate that the odds that the TF element is "absent"/passive are larger than the odds that it is "present"/active. Each bar represents a sample from the dataset. Some of the samples were transfected with siRNA for TIF.gamma. (groups 5 and 6) or SMAD4 (groups 3 and 4) and another set of samples consisted of controls (no transfection, groups 1 and 2). Samples in groups 2, 4 and 6 were stimulated with 5 ng/mL TGF-.beta., and those in groups 1, 3 and 5 were not stimulated. The models using the different target gene lists all correctly predicted for all four target gene lists an increased TGF-.beta. activity in the TGF-.beta.-stimulated samples in groups 2 (controls) and 6 (TIF.gamma.-silenced) and no significant increase in the SMAD-silenced samples (group 4) compared to the corresponding unstimulated samples (see Hesling C. et al., "Antagonistic regulation of EMT by TIF1.gamma. and SMAD4 in mammary epithelial cells", EMBO Reports, Vol. 12, No. 7, 2011, pages 665 to 672). (Legend: 1--Control, no TGF-.beta.; 2--Control, TGF-.beta.; 3--siRNA SMAD4, no TGF-.beta.; 4--siRNA SMAD4, TGF-.beta.; 5--siRNA TIF.gamma., no TGF-.beta.; 6--siRNA TIF.gamma., TGF-.beta.)

[0285] FIG. 17 shows TGF-.beta. cellular signaling pathway activity predictions of the trained exemplary Bayesian network model using the evidence curated list of target genes (see Table 4) for ectocervival epithelial cells (Ect1) from GSE35830, which were stimulated with seminal plasma or 5 ng/mL TGF-.beta.3. In the diagram, the vertical axis indicates the odds that the TF element is "present" resp. "absent", which corresponds to the TGF-.beta. cellular signaling pathway being active resp. passive, wherein values above the horizontal axis correspond to the TF element being more likely "present"/active and values below the horizontal axis indicate that the odds that the TF element is "absent"/passive are larger than the odds that it is "present"/active. Each bar represents a sample from the dataset. Seminal plasma also contains high levels of TGF-131, TGF-.beta.2 and TGF-.beta.3. However, they are predominantly (between 95% and 99%) present in the latent variant, as opposed to the active form (see Sharkey D. J. et al., "TGF-.beta.eta mediates proinflammatory seminal fluid signaling in human cervical epithelial cells", Journal of Immunology, Vol. 189, No. 2, 2012, pages 1024 to 1035). The third and the fourth, i.e., two out of the four, TGF-.beta.3 stimulated samples (group 3) show a strong preference for tumor promoting TGF-.beta. activity, the other two samples, i.e., first and second samples, were found to be more similar to the third and fourth sample of the seminal fluid group (group 2) with cluster analysis. The unstimulated samples (group 1) correctly predicts a passive or tumor suppressing TGF-.beta. activity, whereas the samples stimulated with seminal plasma were predicted to have a TGF-.beta. activity in between which can be caused by the high fraction of latent (i.e., passive) TGF-.beta. isoforms and thus lower stimulation of the TGF-.beta. pathway. (Legend: 1--Control, no TGF-.beta.; 2--Stimulated with 10% seminal plasma; 3--stimulated with 5 ng/mL TGF-.beta.3)

[0286] FIG. 18 shows TGF-.beta. cellular signaling pathway activity predictions of the trained exemplary Bayesian network model using the evidence curated list of target genes (see Table 4) for patient gliomas from GSE16011. In the diagram, the vertical axis indicates the odds that the TF element is "present" resp. "absent", which corresponds to the TGF-.beta. cellular signaling pathway being active resp. passive, wherein values above the horizontal axis correspond to the TF element being more likely "present"/active and values below the horizontal axis indicate that the odds that the TF element is "absent"/passive are larger than the odds that it is "present"/active. Each bar represents a sample from the dataset. It is known from literature that gliomas produce more TGF-.beta. (all isoforms) than normal cells (see Kaminska B. et al., "TGF beta signaling and its role in glioma pathogenesis", Advances in Experimental Medicine and Biology, Vol. 986, 2013, pages 171 to 187). This is also visible in the predicted TGF-.beta. activities which are negative for all controls (group 3), yet in approximately 15% of the gliomas (groups 1, 2, 4-9) a tumor promoting TGF-.beta. was predicted expectedly due to the increased TGF-.beta. secretion in these tumors. (Legend: 1--Astrocytoma (grade II); 2--Astrocytoma (grade III); 3--Control; 4--Glioblastoma multiforme (grade IV); 5--Oligoastrocytic (grade II); 6--Oligoastrocytic (grade III); 7--Oligodendroglial (grade II); 8--Oligodendroglial (grade III); 9--Pilocytic astrocytoma (grade I))

[0287] FIG. 19 shows TGF-.beta. cellular signaling pathway activity predictions of the trained exemplary Bayesian network model using the evidence curated list of target genes (see Table 4) for breast cancer samples from GSE21653. In the diagram, the vertical axis indicates the odds that the TF element is "present" resp. "absent", which corresponds to the TGF-.beta. cellular signaling pathway being active resp. passive, wherein values above the horizontal axis correspond to the TF element being more likely "present"/active and values below the horizontal axis indicate that the odds that the TF element is "absent"/passive are larger than the odds that it is "present"/active. Each bar represents a sample from the dataset. As expected, most breast cancers were predicted to have a passive TGF-.beta. cellular signaling pathway. Also in line with expectations, the highest fraction of TGF-.beta. active or tumor promoting TGF-.beta. activity was found in the basal samples. (Legend: 1--Luminal A; 2--Luminal B; 3--HER2; 4--Basal; 5--Normal-like)

[0288] FIGS. 20 to 23 show TGF-.beta. cellular signaling pathway activity predictions of the trained exemplary Bayesian network models using the evidence curated list of target genes, the 20 target genes shortlist, the 12 target genes shortlist, and the 7 target genes shortlist (see Tables 4 to 7), respectively, for 2D and 3D cultures of A549 lung adenocarcinoma cell lines from GSE42373, which were stimulated with or without 10 ng/mL TNF and 2 ng/mL TGF-.beta.. In the diagram, the vertical axis indicates the odds that the TF element is "present" resp. "absent", which corresponds to the TGF-.beta. cellular signaling pathway being active resp. passive, wherein values above the horizontal axis correspond to the TF element being more likely "present"/active and values below the horizontal axis indicate that the odds that the TF element is "absent"/passive are larger than the odds that it is "present"/active. Each bar represents a sample from the dataset. Cie lik et al., "Epigenetic coordination of signaling pathways during the epithelial-mesenchymal transition", Epigenetics & Chromatin, Vol. 6, No. 1, 2013, demonstrated that in these experiments epithelial-mesenchymal transition (EMT) is efficiently induced in the 3D culture model. This is also demonstrated in the TGF-.beta. cellular signaling pathway activity predictions as both samples from this group (group 4) are the only samples predicted with a tumor promoting TGF-.beta. activity which is known to cause EMT. The control group of the 2D culture without stimulation (group 1) was correctly predicted to have no TGF-.beta. activity, whereas the stimulated 2D culture (group 2) evidently was not able to initiate the TGF-.beta. tumor promoting activity (no EMT), which was also found by Cie lik et al. The unstimulated 3D culture samples (group 3) are also predicted to have a passive TGF-.beta. activity, albeit the odds are very small. (Legend: 1--2D control; 2--2D TGF-.beta. and TNF.alpha.; 3--3D control; 4--3D TGF-.beta. and TNF.alpha.)

[0289] FIG. 24 illustrates overall survival of 284 glioma patients (GSE16011; see also FIG. 18) depicted in a Kaplan-Meier plot. In the diagram, the vertical axis indicates the overall survival as a fraction of the patient group and the horizontal axis indicates time in years. The plot indicates that a tumor-suppressing TGF-.beta. cellular signaling pathway (TGF-.beta. passive, dotted line) is protective for overall survival, whereas having a tumor-promoting TGF-.beta. pathway is associated with significantly higher risk of death (indicated by the steeper slope of the curve). (The patient group with a predicted active TGF-.beta. TF element consisted of 37 patients (solid line), whereas the patient group with a predicted passive TGF-.beta. TF element consisted of 235 patients (dotted line)). The prognostic value of the activity level of the TGF-.beta. TF element is also demonstrated in the hazard ratio of the predicted probability of TGF-.beta. activity: 2.17 (95% CI: 1.44-3.28, p=1.22e-4) and the median survival which is 0.7 years for tumor-promoting TGF-.beta. active patients versus 1.34 years for tumor-suppressing TGF-.beta. patients.

[0290] FIG. 25 illustrates disease free survival of a cohort of 1169 breast cancer patients (GSE6532, GSE9195, E-MTAB-365, GSE20685 and GSE21653; see also FIG. 13 above) depicted in a Kaplan-Meier plot. In the diagram, the vertical axis indicates the disease free survival as a fraction of the patient group and the horizontal axis indicates time in months. The plot indicates that a tumor-suppressing TGF-.beta. cellular signaling pathway (TGF-.beta. passive, dotted line) is protective for disease free survival, whereas having a tumor-promoting TGF-.beta. pathway is associated with significantly higher risk of disease recurrence (indicated by the steeper slope of the curve). (The patient group with a predicted active TGF-.beta. TF element consisted of 103 patients (solid line), whereas the patient group with a predicted passive TGF-.beta. TF element consisted of 1066 patients (dotted line)). The prognostic value of the activity level of the TGF-.beta. TF element is also demonstrated in the hazard ratio of the predicted probability of TGF-.beta. activity: 3.66 (95% CI: 2.37-5.33, p=4.0e-10) and the 75% survival which is 2.3 years for tumor-promoting TGF-.beta. active patients versus 6.4 years for tumor-suppressing TGF-.beta. patients.

[0291] Instead of applying the mathematical model, e.g., the exemplary Bayesian network model, on mRNA input data coming from microarrays or RNA sequencing, it may be beneficial in clinical applications to develop dedicated assays to perform the sample measurements, for instance on an integrated platform using qPCR to determine mRNA levels of target genes. The RNA/DNA sequences of the disclosed target genes can then be used to determine which primers and probes to select on such a platform.

[0292] Validation of such a dedicated assay can be done by using the microarray-based mathematical model as a reference model, and verifying whether the developed assay gives similar results on a set of validation samples. Next to a dedicated assay, this can also be done to build and calibrate similar mathematical models using RNA sequencing data as input measurements.

[0293] The set of target genes which are found to best indicate specific cellular signaling pathway activity, e.g., Tables 4 to 7, based on microarray/RNA sequencing based investigation using the mathematical model, e.g., the exemplary Bayesian network model, can be translated into a multiplex quantitative PCR assay to be performed on a sample of the subject and/or a computer to interpret the expression measurements and/or to infer the activity of the TGF-.beta. cellular signaling pathway. To develop such a test (e.g., FDA-approved or a CLIA waived test in a central service lab or a laboratory developed test for research use only) for cellular signaling pathway activity, development of a standardized test kit is required, which needs to be clinically validated in clinical trials to obtain regulatory approval.

[0294] The present invention relates to a method comprising determining activity of a TGF-.beta. cellular signaling pathway in a subject based at least on expression levels of one or more target gene(s) of the TGF-.beta. cellular signaling pathway measured in a sample of the subject. The present invention further relates to an apparatus comprising a digital processor configured to perform such a method, a non-transitory storage medium storing instructions that are executable by a digital processing device to perform such a method, and a computer program comprising program code means for causing a digital processing device to perform such a method.

[0295] The method may be used, for instance, in diagnosing an (abnormal) activity of the TGF-.beta. cellular signaling pathway, in prognosis based on the determined activity of the TGF-.beta. cellular signaling pathway, in the enrollment of a subject in a clinical trial based on the determined activity of the TGF-.beta. cellular signaling pathway, in the selection of subsequent test(s) to be performed, in the selection of companion diagnostics tests, in clinical decision support systems, or the like. In this regard, reference is made to the published international patent application WO 2013/011479 A2 ("Assessment of cellular signaling pathway activity using probabilistic modeling of target gene expression"), to the published international patent application WO 2014/102668 A2 ("Assessment of cellular signaling pathway activity using linear combination(s) of target gene expressions"), and to Verhaegh W. et al., "Selection of personalized patient therapy through the use of knowledge-based computational models that identify tumor-driving signal transduction pathways", Cancer Research, Vol. 74, No. 11, 2014, pages 2936 to 2945, which describe these applications in more detail.

Example 4

Comparison of the Evidence Curated List with a Broad Literature List

[0296] The list of target genes of the TGF-.beta. cellular signaling pathway constructed based on literature evidence following the procedure as described herein ("evidence curated list of target genes", see Table 4) is compared here with a "broad literature list" of putative target genes of the TGF-.beta. cellular signaling pathway constructed not following above mentioned procedure. The alternative list is a compilation of genes attributed to responding to activity of the TGF-.beta. cellular signaling pathway provided within Thomson-Reuters's Metacore (last accessed May 14, 2013). This database was queried for genes that are transcriptionally regulated directly downstream of the family of SMAD proteins, i.e. SMAD1, SMAD2, SMAD3, SMAD4, SMAD5 and/or SMAD8. This query resulted in 217 unique genes. A further selection was made based on the number of publication references supporting the attributed transcriptional regulation of the respective gene by the SMAD family. Genes that had three or more references were selected for the broad literature list. In other words, no manual curation of the references and no calculation of an evidence score based on the experimental evidence was performed. This procedure resulted in 61 genes, of which a micro-RNA (MIR29B2) not available on the Affymetrix HG-U133Plus2.0 microarray platform and one gene (BGLAP) was not found to have a probeset available on the Affymetrix HG-U133Plus2.0 microarray platform according to the Bioconductor plugin of R. Eventually, this lead to 59 putative target genes which are shown in Table 8 with the associated probesets on the Affymetrix HG-U133Plus2.0 microarray platform.

TABLE-US-00010 TABLE 8 "Broad literature list" of putative target genes of the TGF-.beta. cellular signaling pathway used in the TGF-.beta. cellular signaling pathway models and associated probesets used to measure the mRNA expression level of the genes. Gene Probeset ATF3 1554420_at 1554980_a_at 202672_s_at CCL2 216598_s_at CDH1 201130_s_at 201131_s_at CDKN1A 202284_s_at CDKN2B 207530_s_at 236313_at COL1A2 202403_s_at 202404_s_at 229218_at COL3A1 201852_x_at 211161_s_at 215076_s_at 215077_at 232458_at COL7A1 204136_at 217312_s_at CTGF 209101_at CTNNB1 1554411_at 201533_at 223679_at DLX5 213707_s_at EDN1 1564630_at 218995_s_at 222802_at FN1 1558199_at 210495_x_at 211719_x_at 212464_s_at 214701_s_at 214702_at 216442_x_at FOXP3 221333_at 221334_s_at 224211_at FSHB 214489_at FST 204948_s_at 207345_at 226847_at FSTL3 203592_s_at GNRHR 211522_s_at 211523_at 216341_s_at GSC 1552338_at HAMP 220491_at HEY1 218839_at 44783_s_at IBSP 207370_at 236028_at ID1 208937_s_at ID2 201565_s_at 201566_x_at ID3 207826_s_at IL11 206924_at 206926_s_at IL6 205207_at ITGB1 1553530_a_at 1553678_a_at 211945_s_at 215878_at 215879_at 216178_x_at 216190_x_at ITGB5 201124_at 201125_s_at 214020_x_at 214021_x_at JUN 201464_x_at 201465_s_at 201466_s_at 213281_at JUNB 201473_at LEFTY2 206012_at MTXL1 231746_at MMP13 205959_at MMP9 203936_s_at MSX2 205555_s_at 205556_at 210319_x_at MYC 202431_s_at NKX2-5 206578_at NODAL 220689_at 230916_at 237896_at PDGFB 204200_s_at 216055_at 216061_x_at 217112_at PMEPA1 217875_s_at 222449_at 222450_at PPARG 208510_s_at PTGS2 1554997_a_at 204748_at PTHLH 206300_s_at 210355_at 211756_at SERPINE1 1568765_at 202627_s_at 202628_s_at SKIL 206675_s_at 215889_at 217591_at 225227_at 232379_at SLC25A5 200657_at SMAD6 207069_s_at 209886_s_at 209887_at 213565_s_at SMAD7 204790_at SNAI1 219480_at SNAI2 213139_at SP7 1552340_at SPP1 1568574_x_at 209875_s_at TAGLN 1555724_s_at 205547_s_at 226523_at TERT 1555271_a_at 207199_at TGFBR1 206943_at 224793_s_at 236561_at TIMP1 201666_at VEGFA 210512_s_at 210513_s_at 211527_x_at 212171_x_at VIM 1555938_x_at 201426_s_at

[0297] Subsequently an exemplary Bayesian network model was constructed using the procedure as explained herein. Similarly to the description of the TGF-.beta. cellular signaling pathway model based on the evidence curated list, the conditional probability tables of the edges between probesets and their respective putative target genes of this model including the broad literature list were trained using fRMA processed data from GSE17708. The training results depicted in FIG. 26 show a clear separation between passive (group 1) and active (group 5) training samples. More extreme values of pathway activity are found, especially in group 2 and 3, compared to the training results of the Bayesian model based on the evidence curated lists (see FIGS. 9 to 12). In the diagram, the vertical axis indicates the odds that the TF element is "present" resp. "absent", which corresponds to the TGF-.beta. cellular signaling pathway being active resp. passive, wherein values above the horizontal axis correspond to the TF element being more likely "present"/active and values below the horizontal axis indicate that the odds that the TF element is "absent"/passive are larger than the odds that it is "present"/active. Each bar represents a sample from the dataset. (Legend: 1--Control; 2--TGF-.beta. stimulation with 5 ng/mL for 0.5 h; 3--TGF-.beta. stimulation with 5 ng/mL for 1 h; 4--TGF-.beta. stimulation with 5 ng/mL for 2 h; 5--TGF-.beta. stimulation with 5 ng/mL for 4 h; 6--TGF-.beta. stimulation with 5 ng/mL for 8 h; 7--TGF-.beta. stimulation with 5 ng/mL for 16 h; 8--TGF-.beta. stimulation with 5 ng/mL for 24 h; 9--TGF-.beta. stimulation with 5 ng/mL for 72 h).

[0298] Next the trained exemplary network Bayesian model based on the broad literature list was tested on a number of datasets.

[0299] FIG. 27 shows TGF-.beta. cellular signaling pathway activity predictions of the trained Bayesian network model based on broad literature list for patient gliomas from GSE16011. In the diagram, the vertical axis indicates the odds that the TF element is "present" resp. "absent", which corresponds to the TGF-.beta. cellular signaling pathway being active resp. passive, wherein values above the horizontal axis correspond to the TF element being more likely "present"/active and values below the horizontal axis indicate that the odds that the TF element is "absent"/passive are larger than the odds that it is "present"/active. Each bar represents a sample from the dataset. Although it is known from the literature that gliomas produce more TGF-.beta. (all isoforms) than normal cells (see Kaminska B. et al., "TGF beta signaling and its role in glioma pathogenesis", Advances in Experimental Medicine and Biology, Vol. 986, 2013, pages 171 to 187), the large fraction (>50%) of glioblastoma multiforme (grade IV) patients (group 4) is apparently an overestimation of the number of tumors with an active TGF-.beta. cellular signaling pathway. On the other hand, the TGF-.beta. tumor-promoting activity of all controls (group 3) are correctly predicted to be negative. (Legend: 1--Astrocytoma (grade II); 2--Astrocytoma (grade III); 3--Control; 4--Glioblastoma multiforme (grade IV); 5--Oligoastrocytic (grade II); 6--Oligoastrocytic (grade III); 7--Oligodendroglial (grade II); 8--Oligodendroglial (grade III); 9 Pilocytic astrocytoma (grade I))

[0300] FIG. 28 shows TGF-.beta. cellular signaling pathway activity predictions of the trained Bayesian network model based on broad literature list for breast cancer samples from GSE21653. In the diagram, the vertical axis indicates the odds that the TF element is "present" resp. "absent", which corresponds to the TGF-.beta. cellular signaling pathway being active resp. passive, wherein values above the horizontal axis correspond to the TF element being more likely "present"/active and values below the horizontal axis indicate that the odds that the TF element is "absent"/passive are larger than the odds that it is "present"/active. Each bar represented a sample from the dataset. Unexpectedly, most breast cancer samples were predicted to have a tumor-promoting TGF-.beta. cellular signaling pathway. In addition, the highest fraction of patient samples with tumor-promoting TGF-.beta. activity is found in the luminal A subtype. Luminal A is known to have the best prognosis among the different breast cancer subtypes which does not correspond with the aggressiveness of the TGF-.beta. tumor-promoting activity. (Legend: 1--Luminal A; 2--Luminal B; 3--HER2; 4--Basal; 5--Normal-like)

[0301] As evidenced by the above example, the selection of unique TGF-.beta. target gene sets in combination with the mathematical models described herein for determining the activity level of TGF-.beta. cellular signaling pathway in a sample produces a more robust, precise, and accurate activity status determination than the use of a broader literature list, despite the fact that the number of target genes is larger. By focusing on the specific target genes identified herein, a useful determination of TGF-.beta. cellular signaling pathway activity is provided that can be further used in treatment or prognostic modalities as described herein.

Example 5

Selection of SERPINE1 as Bona Fide TGF-.beta. Target Gene

[0302] A revision of the available literature evidence of TGF-.beta. was performed in January 2015, also including all new scientific papers up to 19 Jan. 2015. Similarly, publications were found using the MEDLINE database of the National Institute of Health accessible at "www.ncbi.nlm.nih.gov/pubmed" using queries such as ("TGF-.beta." AND "target gene"). After manually evaluating the scientific papers for experimental evidence of a number of target genes being a putative target gene of TGF-.beta. using the methodology as described in Example 2 above, a number of putative TGF-.beta. target genes, unexploited in the initial evaluation during the fourth quarter of 2013 and first quarter of 2014, were found. All available experimental evidence was reevaluated and a new ranking of putative target genes was prepared based on the strength of the available experimental evidence for the putative target gene using the methodology as described in Example 2. This resulted in one additional putative TGF-.beta. target gene, SERPINE1, achieving an experimental evidence score above the set threshold. Consequently, SERPINE1 was considered to be a bona fide direct target gene of the TGF-.beta. pathway and tested for improved TGF-.beta. pathway activity level calculations.

[0303] Using two Bayesian networks based on the 11 highest ranked target genes: ANGPTL4, CDC42EP3, CDKN1A, CTGF, GADD45B, ID1, JUNB, SKIL, SMAD7, SNAI2 and VEGFA plus or minus the newly selected SERPINE1 trained using the same data and methodology as described in Example 3 above, resulting in a `11-gene list+SERPINE1` and a `11-gene list` model, respectively.

TABLE-US-00011 TABLE 9 "11-gene list + SERPINE1" (or "revised 12 target genes shortlist" list of target genes of the TGF-.beta. cellular signaling pathway includes: ANGPTL4 CDC42EP3 CDKN1A CTGF GADD45B ID1 JUNB SERPINE1 SKIL SMAD7 SNAI2 VEGFA

TABLE-US-00012 TABLE 10 "11-gene list" of target genes of the TGF-.beta. cellular signaling pathway includes: ANGPTL4 CDC42EP3 CDKN1A CTGF GADD45B ID1 JUNB SKIL SMAD7 SNAI2 VEGFA

[0304] Based on the additional inclusion of the SERPINE1 gene, the target gene lists (See Tables 5 and 7) can be revised into additional non-limiting embodiments, as described in Tables 11 and 12.

TABLE-US-00013 TABLE 11 The "revised 20 target genes shortlist" of target genes of the TGF-.beta. cellular signaling pathway includes: ANGPTL4 CDC42EP3 CDKN1A CTGF GADD45A GADD45B HMGA2 ID1 JUNB PDGFB PTHLH SERPINE1 SGK1 SKIL SMAD4 SMAD5 SMAD6 SMAD7 SNAI2 VEGFA

TABLE-US-00014 TABLE 12 The "revised 7 target genes shortlist" of target genes of the TGF-.beta. cellular signaling pathway includes: ANGPTL4 CDC42EP3 ID1 JUNB SERPINE1 SKIL SMAD7

[0305] Including one more target gene in the mathematical calculation of the pathway activity is expected to have a small effect on the predictions of the pathway activity, which is anticipated to scale the pathway activity level minutely. In the examples below, it is shown that in addition to this anticipated effect there are also markedly different pathway activity levels in several examples which can only be explained by SERPINE1 having an unexpected, advantageous effect on the pathway activity calculations.

[0306] FIGS. 29 and 30 show the predictions of TGF-.beta. activity using both models in Ect1 cell lines stimulated with seminal plasma or 5 ng/mL TGF-.beta.3 or without stimulation from GSE35830. It is clearly visible that including SERPINE1 as an additional target gene improves the capability of the model to detect passive samples with higher accuracy. Furthermore, the model predictions of the second group stimulated with seminal plasma and the third group stimulated with TGF-.beta.3 are more accurate as they predict a higher activity of the TGF-.beta. pathway.

[0307] A second example of improved TGF-.beta. pathway activity predictions is found in A549 lung adenocarcinoma cell line samples grown in 2D and 3D cultures stimulated with or without TNF and TGF-.beta.. The model predictions using both the `11-gene` Bayesian network model and the 11-gene list+SERPINE1' are shown in FIGS. 31 and 32. EMT was only efficiently induced in the 3D culture model with stimulation (group 4). This induction of EMT is diagnosed with a higher accuracy in the `11-gene list+SERPINE1` model compared to the `11-gene list` model, also in case the relative difference between groups 3 and 4 is considered.

[0308] A third example is the TGF-.beta. pathway activity predictions using both models in glioma patients and some control samples from GSE16011. It is known from literature that TGF-.beta. signaling plays a significant role in gliomas (see Kaminska B. et al., "TGF beta signaling and its role in glioma pathogenesis", Advances in Experimental Medicine and Biology, Vol. 986, 2013, pages 171 to 187). The Bayesian network based on `11-gene list+SERPINE1` improves the separation of passive from active samples compared to the `11-gene list` Bayesian network. In addition, a higher fraction of patients is predicted to have an active TGF-.beta. pathway which is more in line with scientific consensus (see e.g. Kaminska et al.). Moreover, the normal brain samples are predicted to have a passive TGF-.beta. with higher probabilities, which is in agreement with the fact that the TGF-.beta. signaling pathway is expected to be in its tumor-suppressive role or passive role.

[0309] The last example demonstrating the improved TGF-.beta. pathway activity predictions by including SERPINE1 in the pathway model is shown by comparing the results of Cox's regression analysis of the 284 glioma patients from GSE16011 using the Bayesian network model based on the `11-gene list+SERPINE1` and `11-gene list`. As shown in FIGS. 33 and 34, the hazard ratio of the probability of TGF-.beta. activity is significantly higher in case the `11-gene list+SERPINE1` is used: 2.57, p=7.87e-10 vs 2.33, p=3.06e-7.

[0310] This specification has been described with reference to embodiments, which are illustrated by the accompanying Examples. The invention can, however, be embodied in different forms and should not be construed as limited to the embodiments set forth herein. Given the teaching herein, one of ordinary skill in the art will be able to modify the invention for a desired purpose and such variations are considered within the scope of the disclosure.

SEQUENCE LISTING

TABLE-US-00015 [0311] Seq. No. Gene: Seq. 1 ANGPTL4 Seq. 2 ATF3 Seq. 3 CCL2 Seq. 4 CDC42EP3 Seq. 5 CDH1 Seq. 6 CDKN1A Seq. 7 CDKN2B Seq. 8 COL1A2 Seq. 9 COL3A1 Seq. 10 COL7A1 Seq. 11 CTGF Seq. 12 CTNNB1 Seq. 13 DLX5 Seq. 14 EDN1 Seq. 15 FN1 Seq. 16 FOXP3 Seq. 17 FSHB Seq. 18 FST Seq. 19 FSTL3 Seq. 20 GADD45A Seq. 21 GADD45B Seq. 22 GNRHR Seq. 23 GSC Seq. 24 HAMP Seq. 25 HEY1 Seq. 26 HMGA2 Seq. 27 IBSP Seq. 28 ID1 Seq. 29 ID2 Seq. 30 ID3 Seq. 31 IL11 Seq. 32 IL6 Seq. 33 INPP5D Seq. 34 ITGB1 Seq. 35 ITGB5 Seq. 36 JUN Seq. 37 JUNB Seq. 38 LEFTY2 Seq. 39 MIXL1 Seq. 40 MMP13 Seq. 41 MMP2 Seq. 42 MMP9 Seq. 43 MSX2 Seq. 44 MYC Seq. 45 NKX2-5 Seq. 46 NODAL Seq. 47 OVOL1 Seq. 48 PDGFB Seq. 49 PMEPA1 Seq. 50 PPARG Seq. 51 PTGS2 Seq. 52 PTHLH Seq. 53 SERPINE1 Seq. 54 SGK1 Seq. 55 SKIL Seq. 56 SLC25A5 Seq. 57 SMAD4 Seq. 58 SMAD5 Seq. 59 SMAD6 Seq. 60 SMAD7 Seq. 61 SNAI1 Seq. 62 SNAI2 Seq. 63 SP7 Seq. 64 SPP1 Seq. 65 TAGLN Seq. 66 TERT Seq. 67 TGFBR1 Seq. 68 TIMP1 Seq. 69 VEGFA Seq. 70 VIM Seq. 71 SERPINE1

Sequence CWU 1

1

14311905DNAHomo sapiens 1ataaaaaccg tcctcgggcg cggcggggag aagccgagct gagcggatcc tcacacgact 60gtgatccgat tctttccagc ggcttctgca accaagcggg tcttaccccc ggtcctccgc 120gtctccagtc ctcgcacctg gaaccccaac gtccccgaga gtccccgaat ccccgctccc 180aggctaccta agaggatgag cggtgctccg acggccgggg cagccctgat gctctgcgcc 240gccaccgccg tgctactgag cgctcagggc ggacccgtgc agtccaagtc gccgcgcttt 300gcgtcctggg acgagatgaa tgtcctggcg cacggactcc tgcagctcgg ccaggggctg 360cgcgaacacg cggagcgcac ccgcagtcag ctgagcgcgc tggagcggcg cctgagcgcg 420tgcgggtccg cctgtcaggg aaccgagggg tccaccgacc tcccgttagc ccctgagagc 480cgggtggacc ctgaggtcct tcacagcctg cagacacaac tcaaggctca gaacagcagg 540atccagcaac tcttccacaa ggtggcccag cagcagcggc acctggagaa gcagcacctg 600cgaattcagc atctgcaaag ccagtttggc ctcctggacc acaagcacct agaccatgag 660gtggccaagc ctgcccgaag aaagaggctg cccgagatgg cccagccagt tgacccggct 720cacaatgtca gccgcctgca ccggctgccc agggattgcc aggagctgtt ccaggttggg 780gagaggcaga gtggactatt tgaaatccag cctcaggggt ctccgccatt tttggtgaac 840tgcaagatga cctcagatgg aggctggaca gtaattcaga ggcgccacga tggctcagtg 900gacttcaacc ggccctggga agcctacaag gcggggtttg gggatcccca cggcgagttc 960tggctgggtc tggagaaggt gcatagcatc acgggggacc gcaacagccg cctggccgtg 1020cagctgcggg actgggatgg caacgccgag ttgctgcagt tctccgtgca cctgggtggc 1080gaggacacgg cctatagcct gcagctcact gcacccgtgg ccggccagct gggcgccacc 1140accgtcccac ccagcggcct ctccgtaccc ttctccactt gggaccagga tcacgacctc 1200cgcagggaca agaactgcgc caagagcctc tctggaggct ggtggtttgg cacctgcagc 1260cattccaacc tcaacggcca gtacttccgc tccatcccac agcagcggca gaagcttaag 1320aagggaatct tctggaagac ctggcggggc cgctactacc cgctgcaggc caccaccatg 1380ttgatccagc ccatggcagc agaggcagcc tcctagcgtc ctggctgggc ctggtcccag 1440gcccacgaaa gacggtgact cttggctctg cccgaggatg tggccgttcc ctgcctgggc 1500aggggctcca aggaggggcc atctggaaac ttgtggacag agaagaagac cacgactgga 1560gaagccccct ttctgagtgc aggggggctg catgcgttgc ctcctgagat cgaggctgca 1620ggatatgctc agactctaga ggcgtggacc aaggggcatg gagcttcact ccttgctggc 1680cagggagttg gggactcaga gggaccactt ggggccagcc agactggcct caatggcgga 1740ctcagtcaca ttgactgacg gggaccaggg cttgtgtggg tcgagagcgc cctcatggtg 1800ctggtgctgt tgtgtgtagg tcccctgggg acacaagcag gcgccaatgg tatctgggcg 1860gagctcacag agttcttgga ataaaagcaa cctcagaaca ctttg 190522088DNAHomo sapiens 2tccgctccgt tcggccggtt ctcccgggaa gctattaata gcattacgtc agcctgggac 60tggcaacacg gagtaaacga ccgcgccgcc agcctgaggg ctataaaagg ggtgatgcaa 120cgctctccaa gccacagtcg cacgcagcca ggcgcgcact gcacagctct cttctctcgc 180cgccgcccga gcgcaccctt cagcccgcgc gccggccgtg agtcctcggt gctcgcccgc 240cggccagaca aacagcccgc ccgaccccgt cccgaccctg gccgccccga gcggagcctg 300gagcaaaatg atgcttcaac acccaggcca ggtctctgcc tcggaagtga gtgcttctgc 360catcgtcccc tgcctgtccc ctcctgggtc actggtgttt gaggattttg ctaacctgac 420gccctttgtc aaggaagagc tgaggtttgc catccagaac aagcacctct gccaccggat 480gtcctctgcg ctggaatcag tcactgtcag cgacagaccc ctcggggtgt ccatcacaaa 540agccgaggta gcccctgaag aagatgaaag gaaaaagagg cgacgagaaa gaaataagat 600tgcagctgca aagtgccgaa acaagaagaa ggagaagacg gagtgcctgc agaaagagtc 660ggagaagctg gaaagtgtga atgctgaact gaaggctcag attgaggagc tcaagaacga 720gaagcagcat ttgatataca tgctcaacct tcatcggccc acgtgtattg tccgggctca 780gaatgggagg actccagaag atgagagaaa cctctttatc caacagataa aagaaggaac 840attgcagagc taagcagtcg tggtatgggg gcgactgggg agtcctcatt gaatcctcat 900tttataccca aaaccctgaa gccattggag agctgtcttc ctgtgtacct ctagaatccc 960agcagcagag aaccatcaag gcgggagggc ctgcagtgat tcagcaggcc cttcccattc 1020tgccccagag tgggtcttgg accagggcaa gtgcatcttt gcctcaactc caggatttag 1080gccttaacac actggccatt cttatgttcc agatggcccc cagctggtgt cctgcccgcc 1140tttcatctgg attctacaaa aaaccaggat gcccaccgtt aggattcagg cagcagtgtc 1200tgtacctcgg gtgggaggga tggggccatc tccttcaccg tggctaccat tgtcactcgt 1260aggggatgtg gagtgagaac agcatttagt gaagttgtgc aacggccagg gttgtgcttt 1320ctagcaaata tgctgttatg tccagaaatt gtgtgtgcaa gaaaactagg caatgtactc 1380ttccgatgtt tgtgtcacac aacactgatg tgacttttat atgctttttc tcagatctgg 1440tttctaagag ttttgggggg cggggctgtc accacgtgca gtatctcaag atattcaggt 1500ggccagaaga gcttgtcagc aagaggagga cagaattctc ccagcgttaa cacaaaatcc 1560atgggcagta tgatggcagg tcctctgttg caaactcagt tccaaagtca caggaagaaa 1620gcagaaagtt caacttccaa agggttagga ctctccactc aatgtcttag gtcaggagtt 1680gtgtctaggc tggaagagcc aaagaatatt ccattttcct ttccttgtgg ttgaaaacca 1740cagtcagtgg agagatgttt ggaaaccaca gtcagtggag cctgggtggt acccaggctt 1800tagcattatt ggatgtcaat agcattgttt ttgtcatgta gctgttttaa gaaatctggc 1860ccagggtgtt tgcagctgtg agaagtcact cacactggcc acaaggacgc tggctactgt 1920ctattaaaat tctgatgttt ctgtgaaatt ctcagagtgt ttaattgtac tcaatggtat 1980cattacaatt ttctgtaaga gaaaatatta cttatttatc ctagtattcc taacctgtca 2040gaataataaa tattggaacc aagacatggt aaacaaaaaa aaaaaaaa 20883760DNAHomo sapiens 3gaggaaccga gaggctgaga ctaacccaga aacatccaat tctcaaactg aagctcgcac 60tctcgcctcc agcatgaaag tctctgccgc ccttctgtgc ctgctgctca tagcagccac 120cttcattccc caagggctcg ctcagccaga tgcaatcaat gccccagtca cctgctgtta 180taacttcacc aataggaaga tctcagtgca gaggctcgcg agctatagaa gaatcaccag 240cagcaagtgt cccaaagaag ctgtgatctt caagaccatt gtggccaagg agatctgtgc 300tgaccccaag cagaagtggg ttcaggattc catggaccac ctggacaagc aaacccaaac 360tccgaagact tgaacactca ctccacaacc caagaatctg cagctaactt attttcccct 420agctttcccc agacaccctg ttttatttta ttataatgaa ttttgtttgt tgatgtgaaa 480cattatgcct taagtaatgt taattcttat ttaagttatt gatgttttaa gtttatcttt 540catggtacta gtgtttttta gatacagaga cttggggaaa ttgcttttcc tcttgaacca 600cagttctacc cctgggatgt tttgagggtc tttgcaagaa tcattaatac aaagaatttt 660ttttaacatt ccaatgcatt gctaaaatat tattgtggaa atgaatattt tgtaactatt 720acaccaaata aatatatttt tgtacaaaaa aaaaaaaaaa 76045715DNAHomo sapiens 4cgcgcccacc ggagcccggg ctgagaggga cctggggagc tgcggcctgg ccggggcggc 60gcactcaggt ggcctcgctt ccctgcgggt caccgcccgc cactcgcaca gctaggtcgg 120cctgttggga tcgggagagg tgggcgcacg agttttagtg cgggagtccg gggtgcgggc 180ggagtcctat tgtccccgtg cacccgggcg gcagcacctc cgggtccctc tttaaaccga 240gcgtccggcg acctttcttt gtgcttaggg agtcgaaagc ggcatcttct ccgagagaag 300tcgcctactg gggggtggcg ctggggaggt aacaatgggc gcccattgtc ctccgagggt 360ccaacggtga cccccccccg cgcgcgcgcc cggccaccgg ttggccccgg gccagggcac 420aggtaccgcg gctgggaggg tcggccccgc tgcccgcgcc ctccgccccg ccccagtgag 480tccccgcgcc gccggccccg ccccgcgccg ccccgccctc cgcaggttca gtcctcgcgt 540ccggccgccc cgcgctcagt cgcgcgcacc ttctctcgcg gccgggggac cgcagcgcgg 600ggctagcccg gagacccggc caccggcctg gggcgccttc acgccgtctc ggagcggata 660atgcggtgag caggcaccac gccggcagac tcggctggat ctgcgcacag cggcagggat 720tgcgtgcgcc cgcgggaggc ccggggcagc ggctgggatc ctcagcggcg gccggtttgt 780cctggttgtg gtcaagactg gatgatgtaa ctggctctct aggaagcctc acttggccgt 840aacctcagga aggttctctt tgaccccatc tcatttcgaa gccacttctg aagccacttg 900agaaaaatga tgtgacagtt cctatcaaaa aggattcaga aacatatacc atctgtgaag 960aaagtggccc tttctcccgc ttgcaaaata gacattctca aattccaaaa tgccagccaa 1020gaccccaatt tacctgaaag cagccaataa caagaaagga aagaaattta aactgaggga 1080cattctgtct cctgatatga tcagtccccc gcttggagac tttcgccaca ccatccacat 1140tggcaaagag ggccagcacg atgtctttgg agatatttcc tttcttcaag ggaactacga 1200gcttttacct ggaaaccagg agaaagcaca cctgggccag ttccctgggc ataatgagtt 1260cttccgggcc aacagcacct cggactctgt gttcacagaa acgccctccc cggtgctcaa 1320aaatgccatc tccctcccga ccattggagg atcccaagct ctcatgttgc ccttattgtc 1380accagtgaca tttaattcca aacaggagtc cttcgggcca gcaaagctgc ccaggcttag 1440ctgcgagccc gtcatggagg aaaaagctca ggagaaaagc agtctgttgg agaatgggac 1500agtccaccag ggagacacct cgtggggctc cagcggttct gcatctcagt ccagccaagg 1560cagagacagc cactcctcca gcctgtccga acagtacccc gactggccag ccgaggacat 1620gtttgaccat cccaccccat gcgagctcat caagggaaag actaagtcag aggagtccct 1680ctctgacctt acaggttccc tcctctccct gcagcttgat cttgggccct cacttttgga 1740tgaggtgctg aatgtaatgg ataaaaataa gtaacaagat gccaactttt ttcctttggg 1800gtaaaaggta caaaaacaaa ctaaccacag ttgaagagaa gggcttccgg agctgtattt 1860gcagttttgt gttgggtttt ctaaaataat attcttacaa agtatttttt tacctgttat 1920gccctgtttg caaaaacaat ttagaaaaaa acaacaaagc aaaacctatc ttggcaaaaa 1980aaggaagtga gtcagagccc attttcagga ggcattggtg atgttcggct cacatattgt 2040ttgcagacac acaagaaatc tggcttggcc aggattggca ctagctatga agggctgagc 2100gagtcacatt aaggaacttc acggaacttt atagcactcc gacattttct gagcaagagg 2160aagtcaaaat ttatttaaca cctaagcctt tttgtagact cttttctata tattgcttag 2220gctcaccata gcgaattctc cagtgttaaa acttttctgt tttcacattt gaactttatg 2280ggttttgggg attttcttgt agttcttata tatccctata tattatatct atattgcaaa 2340attttgactg tcagctacat gttggtaaga cacaggcaaa gtattactgt aactaagtta 2400tttttaaagt taaaatatat ttttacgtgc ctttggcttt ttattgcaga gtctacattt 2460tatagattct acatcagatg ttgtcactta tttccattgg gattccattg taagctgtgt 2520atgtgcgtgt ttggaaaagt gtattcatac ttagtttttt tttcttcatc tgttatcata 2580cttttaacag caaccaataa cggattgtaa agtgtaaagg cacaggttac tcatgatgct 2640tctgcagaga ctgtgggcta caccacatat gttatttgga aatataggta ttttagtaca 2700gtacatactt gcattacata ggtacttcaa gcaacacaat aaaaagtaaa tgataaagtg 2760aacttgcttg tttatagtaa taaacaagac cataagagaa taagtatagc tagagaaatt 2820gcttctctga aatgtacatg agcccttaag gtaagagatg atttccatct actctcattt 2880tgattacttc cttatggttt gagaggctag aaactgagcc tctctacttt tggaaaaatg 2940aacatgtgag gtcagatttt tttttttttt tttaagtcag cactgatgcc accctctcag 3000tggtcatttc tgagcatctt cctgacttga acaccttcta cagcaaactc ttgcaagtcc 3060agtttcatcc ctgtaaggca aatgtctttt cacgcagaaa gtgccatata gacgagataa 3120aggcagctaa aacgagggca gtagagagca cttacccgac cccaaggtgc cagagatgcc 3180ctgaggatgg tggttaagga aacaggagca ggaaatgtac acacagattc ctgtcccttt 3240gccaactact ccttccccat caaagaaaaa cacttgcaca cagtaactac cagctccttc 3300tctcaaactt gtatttctcc tggaaatgta tctcagaaat gacctcctct cccaaccact 3360tcaacgattc tttctttggg tttggggttc ttgcagttct atcatctaaa ataacctttg 3420gactgcaggt aaaatgcaat taggacaact aaccaagtag acgaaacaag ttcccctagg 3480caggggtgtc caatatttta gcttccctgg accgcattgg aagaattttc ttgggccaca 3540tgtaaaacac actaacacta accatagttg atgagcttaa aaaaataaaa atagaaaatt 3600gcaaaaaaaa aaaaaaaaaa aaatctcaga ctgttttaag aaagtttaaa aatttgtgtt 3660ggacttcatg cgggccacag gttggacaag cttgccctag ggcattgtgt gctttccgta 3720acttctcagt tgtatttcgt tatccatgac tctccagtgt tttttctgtt ggaccacacc 3780cgtcacagtt cacagttcca aagagaaatt tcccagccta ttctaaatct tgttaatgac 3840gaagagtcca atgtatctca ttatttgtag ccaattttag actcttttca atacctcccc 3900cccattttaa ttagtattga tcatattcag tctttcattt tactcttcat ctgtagcgtg 3960acctcaaggt aaagatgaaa ctatttcatg aaaaggggag gagtatggct gtgcattagc 4020tctactccct ctctggtaag tactggggag agaacagccc tgccagtact gggtttgata 4080gattctaaat attaatcaca catcctgcct acagttagcc attttagttt ctgggagttc 4140tttcatgtac attttcttcc attaattgaa ttaggtataa ttgagatggc aataaatatg 4200cccgtattag aaagaggaaa caaagctaca tgcggcttat gattttgttg agtcacttct 4260cccgaggcag cctttccaat gcctggtccc ttcccctgag agcaggtgga ctgctggtgg 4320tggctttctt tcctgcagag aggcacttta gacccatacc tgctgtgagc tgaattgatg 4380ttctcatcct gtgaaccttc tcccacttta acctaattta tctttacttg tttaaagata 4440aggaaaccca agatgtactt tatttgcaaa ctcaaagcaa atggcgagcc acctgtgacc 4500cagtaaccag aaaagaaacc atgccatttg tataagtaga gacacttctt gttgaggtag 4560gcaaggctct tgtgagcgat ttttttcccc tagtgagacc taacaaaaga caagctatat 4620catttctgcc tgaaattatc tgcttgaaaa gatcaaaata tcaggatact tagctcttca 4680caaatatgaa gtcattatca catttcactg agccagaaat cactgttaac agcacacaca 4740aaagactaca ctggttgaac agcaaagaga aacccgggtc tccagaatca cagtttagtc 4800cttctatatt actgcaagtg acctgttttt tctgaaggct ccccgcaaat gaagtcctgg 4860aatggaaaaa atccataagt ccataaatta acttgataaa tattttagaa cagacaaaag 4920aaaatattga gtgatgtagt tctaatcctc ctaatatgga acctggcaag actgaatcat 4980tttactgtga aatatataaa cacaatagaa tgagccaaca tgatggtttc tctccagtaa 5040gagtttttct tttggaaatg aggttaacct agccccaaat ctagcaattc tcataaaatc 5100cgattttaga attagcctcc cagattaatc tgaatgattg acttattttt tcttaggcaa 5160gtcagtaagc cacccactag acagccatat ccagcaaaat aagagaagtt tccagatgcc 5220aaatgataag ccaccatcaa cccagcgggg aagccttctg gttggtttgg ctgtatgaga 5280ttcaggaagg ccagaatacc caaaattatt cacacgacgt taacttattg gtactggcta 5340agcaatacat gtatttccta aaggaggaga tggtcttttg gttgatttat ggacacactt 5400gtttcatctg actgtaaata tattgcatgc tttattctga tggtgcacta tttcatccag 5460caagcttttc atctgagaat gtttaatgtt gaccttattc ttagagcaag tagatctaaa 5520tatttttcag ctgagttatt agggagtcat tattctgtgg tacaatgctg caaaaagcat 5580catgtggaag aatgggaact atgcttactt tatgaagtga tgtataacac aatgaaatct 5640gttttacaac tactgtgctg catttaatta tcttccattt ttgctgttaa aaaaaaaaaa 5700tccgttaatg atgtc 571554815DNAHomo sapiens 5agtggcgtcg gaactgcaaa gcacctgtga gcttgcggaa gtcagttcag actccagccc 60gctccagccc ggcccgaccc gaccgcaccc ggcgcctgcc ctcgctcggc gtccccggcc 120agccatgggc ccttggagcc gcagcctctc ggcgctgctg ctgctgctgc aggtctcctc 180ttggctctgc caggagccgg agccctgcca ccctggcttt gacgccgaga gctacacgtt 240cacggtgccc cggcgccacc tggagagagg ccgcgtcctg ggcagagtga attttgaaga 300ttgcaccggt cgacaaagga cagcctattt ttccctcgac acccgattca aagtgggcac 360agatggtgtg attacagtca aaaggcctct acggtttcat aacccacaga tccatttctt 420ggtctacgcc tgggactcca cctacagaaa gttttccacc aaagtcacgc tgaatacagt 480ggggcaccac caccgccccc cgccccatca ggcctccgtt tctggaatcc aagcagaatt 540gctcacattt cccaactcct ctcctggcct cagaagacag aagagagact gggttattcc 600tcccatcagc tgcccagaaa atgaaaaagg cccatttcct aaaaacctgg ttcagatcaa 660atccaacaaa gacaaagaag gcaaggtttt ctacagcatc actggccaag gagctgacac 720accccctgtt ggtgtcttta ttattgaaag agaaacagga tggctgaagg tgacagagcc 780tctggataga gaacgcattg ccacatacac tctcttctct cacgctgtgt catccaacgg 840gaatgcagtt gaggatccaa tggagatttt gatcacggta accgatcaga atgacaacaa 900gcccgaattc acccaggagg tctttaaggg gtctgtcatg gaaggtgctc ttccaggaac 960ctctgtgatg gaggtcacag ccacagacgc ggacgatgat gtgaacacct acaatgccgc 1020catcgcttac accatcctca gccaagatcc tgagctccct gacaaaaata tgttcaccat 1080taacaggaac acaggagtca tcagtgtggt caccactggg ctggaccgag agagtttccc 1140tacgtatacc ctggtggttc aagctgctga ccttcaaggt gaggggttaa gcacaacagc 1200aacagctgtg atcacagtca ctgacaccaa cgataatcct ccgatcttca atcccaccac 1260gtacaagggt caggtgcctg agaacgaggc taacgtcgta atcaccacac tgaaagtgac 1320tgatgctgat gcccccaata ccccagcgtg ggaggctgta tacaccatat tgaatgatga 1380tggtggacaa tttgtcgtca ccacaaatcc agtgaacaac gatggcattt tgaaaacagc 1440aaagggcttg gattttgagg ccaagcagca gtacattcta cacgtagcag tgacgaatgt 1500ggtacctttt gaggtctctc tcaccacctc cacagccacc gtcaccgtgg atgtgctgga 1560tgtgaatgaa gcccccatct ttgtgcctcc tgaaaagaga gtggaagtgt ccgaggactt 1620tggcgtgggc caggaaatca catcctacac tgcccaggag ccagacacat ttatggaaca 1680gaaaataaca tatcggattt ggagagacac tgccaactgg ctggagatta atccggacac 1740tggtgccatt tccactcggg ctgagctgga cagggaggat tttgagcacg tgaagaacag 1800cacgtacaca gccctaatca tagctacaga caatggttct ccagttgcta ctggaacagg 1860gacacttctg ctgatcctgt ctgatgtgaa tgacaacgcc cccataccag aacctcgaac 1920tatattcttc tgtgagagga atccaaagcc tcaggtcata aacatcattg atgcagacct 1980tcctcccaat acatctccct tcacagcaga actaacacac ggggcgagtg ccaactggac 2040cattcagtac aacgacccaa cccaagaatc tatcattttg aagccaaaga tggccttaga 2100ggtgggtgac tacaaaatca atctcaagct catggataac cagaataaag accaagtgac 2160caccttagag gtcagcgtgt gtgactgtga aggggccgct ggcgtctgta ggaaggcaca 2220gcctgtcgaa gcaggattgc aaattcctgc cattctgggg attcttggag gaattcttgc 2280tttgctaatt ctgattctgc tgctcttgct gtttcttcgg aggagagcgg tggtcaaaga 2340gcccttactg cccccagagg atgacacccg ggacaacgtt tattactatg atgaagaagg 2400aggcggagaa gaggaccagg actttgactt gagccagctg cacaggggcc tggacgctcg 2460gcctgaagtg actcgtaacg acgttgcacc aaccctcatg agtgtccccc ggtatcttcc 2520ccgccctgcc aatcccgatg aaattggaaa ttttattgat gaaaatctga aagcggctga 2580tactgacccc acagccccgc cttatgattc tctgctcgtg tttgactatg aaggaagcgg 2640ttccgaagct gctagtctga gctccctgaa ctcctcagag tcagacaaag accaggacta 2700tgactacttg aacgaatggg gcaatcgctt caagaagctg gctgacatgt acggaggcgg 2760cgaggacgac taggggactc gagagaggcg ggccccagac ccatgtgctg ggaaatgcag 2820aaatcacgtt gctggtggtt tttcagctcc cttcccttga gatgagtttc tggggaaaaa 2880aaagagactg gttagtgatg cagttagtat agctttatac tctctccact ttatagctct 2940aataagtttg tgttagaaaa gtttcgactt atttcttaaa gctttttttt ttttcccatc 3000actctttaca tggtggtgat gtccaaaaga tacccaaatt ttaatattcc agaagaacaa 3060ctttagcatc agaaggttca cccagcacct tgcagatttt cttaaggaat tttgtctcac 3120ttttaaaaag aaggggagaa gtcagctact ctagttctgt tgttttgtgt atataatttt 3180ttaaaaaaaa tttgtgtgct tctgctcatt actacactgg tgtgtccctc tgcctttttt 3240ttttttttaa gacagggtct cattctatcg gccaggctgg agtgcagtgg tgcaatcaca 3300gctcactgca gccttgtcct cccaggctca agctatcctt gcacctcagc ctcccaagta 3360gctgggacca caggcatgca ccactacgca tgactaattt tttaaatatt tgagacgggg 3420tctccctgtg ttacccaggc tggtctcaaa ctcctgggct caagtgatcc tcccatcttg 3480gcctcccaga gtattgggat tacagacatg agccactgca cctgcccagc tccccaactc 3540cctgccattt tttaagagac agtttcgctc catcgcccag gcctgggatg cagtgatgtg 3600atcatagctc actgtaacct caaactctgg ggctcaagca gttctcccac cagcctcctt 3660tttatttttt tgtacagatg gggtcttgct atgttgccca agctggtctt aaactcctgg 3720cctcaagcaa tccttctgcc ttggcccccc aaagtgctgg gattgtgggc atgagctgct 3780gtgcccagcc tccatgtttt aatatcaact ctcactcctg aattcagttg ctttgcccaa 3840gataggagtt ctctgatgca gaaattattg ggctctttta gggtaagaag tttgtgtctt 3900tgtctggcca catcttgact aggtattgtc tactctgaag acctttaatg gcttccctct 3960ttcatctcct gagtatgtaa cttgcaatgg gcagctatcc agtgacttgt tctgagtaag 4020tgtgttcatt aatgtttatt tagctctgaa gcaagagtga tatactccag gacttagaat 4080agtgcctaaa gtgctgcagc caaagacaga gcggaactat gaaaagtggg cttggagatg 4140gcaggagagc ttgtcattga gcctggcaat ttagcaaact gatgctgagg atgattgagg 4200tgggtctacc tcatctctga aaattctgga aggaatggag gagtctcaac atgtgtttct 4260gacacaagat ccgtggtttg tactcaaagc ccagaatccc caagtgcctg cttttgatga 4320tgtctacaga aaatgctggc tgagctgaac acatttgccc aattccaggt gtgcacagaa 4380aaccgagaat attcaaaatt

ccaaattttt ttcttaggag caagaagaaa atgtggccct 4440aaagggggtt agttgagggg tagggggtag tgaggatctt gatttggatc tctttttatt 4500taaatgtgaa tttcaacttt tgacaatcaa agaaaagact tttgttgaaa tagctttact 4560gtttctcaag tgttttggag aaaaaaatca accctgcaat cactttttgg aattgtcttg 4620atttttcggc agttcaagct atatcgaata tagttctgtg tagagaatgt cactgtagtt 4680ttgagtgtat acatgtgtgg gtgctgataa ttgtgtattt tctttggggg tggaaaagga 4740aaacaattca agctgagaaa agtattctca aagatgcatt tttataaatt ttattaaaca 4800attttgttaa accat 481562122DNAHomo sapiens 6ggtggctatt ttgtccttgg gctgcctgtt ttcagctgct gcaaccacag ggatttcttc 60tgttcaggcg ccatgtcaga accggctggg gatgtccgtc agaacccatg cggcagcaag 120gcctgccgcc gcctcttcgg cccagtggac agcgagcagc tgagccgcga ctgtgatgcg 180ctaatggcgg gctgcatcca ggaggcccgt gagcgatgga acttcgactt tgtcaccgag 240acaccactgg agggtgactt cgcctgggag cgtgtgcggg gccttggcct gcccaagctc 300taccttccca cggggccccg gcgaggccgg gatgagttgg gaggaggcag gcggcctggc 360acctcacctg ctctgctgca ggggacagca gaggaagacc atgtggacct gtcactgtct 420tgtacccttg tgcctcgctc aggggagcag gctgaagggt ccccaggtgg acctggagac 480tctcagggtc gaaaacggcg gcagaccagc atgacagatt tctaccactc caaacgccgg 540ctgatcttct ccaagaggaa gccctaatcc gcccacagga agcctgcagt cctggaagcg 600cgagggcctc aaaggcccgc tctacatctt ctgccttagt ctcagtttgt gtgtcttaat 660tattatttgt gttttaattt aaacacctcc tcatgtacat accctggccg ccccctgccc 720cccagcctct ggcattagaa ttatttaaac aaaaactagg cggttgaatg agaggttcct 780aagagtgctg ggcattttta ttttatgaaa tactatttaa agcctcctca tcccgtgttc 840tccttttcct ctctcccgga ggttgggtgg gccggcttca tgccagctac ttcctcctcc 900ccacttgtcc gctgggtggt accctctgga ggggtgtggc tccttcccat cgctgtcaca 960ggcggttatg aaattcaccc cctttcctgg acactcagac ctgaattctt tttcatttga 1020gaagtaaaca gatggcactt tgaaggggcc tcaccgagtg ggggcatcat caaaaacttt 1080ggagtcccct cacctcctct aaggttgggc agggtgaccc tgaagtgagc acagcctagg 1140gctgagctgg ggacctggta ccctcctggc tcttgatacc cccctctgtc ttgtgaaggc 1200agggggaagg tggggtcctg gagcagacca ccccgcctgc cctcatggcc cctctgacct 1260gcactgggga gcccgtctca gtgttgagcc ttttccctct ttggctcccc tgtacctttt 1320gaggagcccc agctaccctt cttctccagc tgggctctgc aattcccctc tgctgctgtc 1380cctccccctt gtcctttccc ttcagtaccc tctcagctcc aggtggctct gaggtgcctg 1440tcccaccccc acccccagct caatggactg gaaggggaag ggacacacaa gaagaagggc 1500accctagttc tacctcaggc agctcaagca gcgaccgccc cctcctctag ctgtgggggt 1560gagggtccca tgtggtggca caggccccct tgagtggggt tatctctgtg ttaggggtat 1620atgatggggg agtagatctt tctaggaggg agacactggc ccctcaaatc gtccagcgac 1680cttcctcatc caccccatcc ctccccagtt cattgcactt tgattagcag cggaacaagg 1740agtcagacat tttaagatgg tggcagtaga ggctatggac agggcatgcc acgtgggctc 1800atatggggct gggagtagtt gtctttcctg gcactaacgt tgagcccctg gaggcactga 1860agtgcttagt gtacttggag tattggggtc tgaccccaaa caccttccag ctcctgtaac 1920atactggcct ggactgtttt ctctcggctc cccatgtgtc ctggttcccg tttctccacc 1980tagactgtaa acctctcgag ggcagggacc acaccctgta ctgttctgtg tctttcacag 2040ctcctcccac aatgctgaat atacagcagg tgctcaataa atgattctta gtgactttac 2100ttgtaaaaaa aaaaaaaaaa aa 212273878DNAHomo sapiens 7ggctccccac tctgccagag cgaggcgggg cagtgaggac tccgcgacgc gtccgcaccc 60tgcggccaga gcggctttga gctcggctgc gtccgcgcta ggcgcttttt cccagaagca 120atccaggcgc gcccgctggt tcttgagcgc caggaaaagc ccggagctaa cgaccggccg 180ctcggccact gcacggggcc ccaagccgca gaaggacgac gggagggtaa tgaagctgag 240cccaggtctc ctaggaagga gagagtgcgc cggagcagcg tgggaaagaa gggaagagtg 300tcgttaagtt tacggccaac ggtggattat ccgggccgct gcgcgtctgg gggctgcgga 360atgcgcgagg agaacaaggg catgcccagt gggggcggca gcgatgaggg tctggccagc 420gccgcggcgc ggggactagt ggagaaggtg cgacagctcc tggaagccgg cgcggatccc 480aacggagtca accgtttcgg gaggcgcgcg atccaggtca tgatgatggg cagcgcccgc 540gtggcggagc tgctgctgct ccacggcgcg gagcccaact gcgcagaccc tgccactctc 600acccgaccgg tgcatgatgc tgcccgggag ggcttcctgg acacgctggt ggtgctgcac 660cgggccgggg cgcggctgga cgtgcgcgat gcctggggtc gtctgcccgt ggacttggcc 720gaggagcggg gccaccgcga cgttgcaggg tacctgcgca cagccacggg ggactgacgc 780caggttcccc agccgcccac aacgacttta ttttcttacc caatttccca cccccaccca 840cctaattcga tgaaggctgc caacggggag cggcggaaag cctgtaagcc tgcaagcctg 900tctgagactc acaggaagga ggagccgacc gggaataacc ttccatacat ttttttcttt 960gtcttatctg gccctcgaca ctcaccatga agcgaaacac agagaagcgg atttccaggg 1020atatttagga gtgtgtgaca ttccaggggt cgtttgcttt tcagggtttt ctgagggaaa 1080gtgcatatga aatccttgac tggacctggt ggctacgaat cttccgatgg atgaatctcc 1140cactccagcg ctgagtggga gaaggcagtg attagcactt gggtgacggc agtcgatgcg 1200ttcactccaa tgtctgctga ggagttatgg tgaacccaca acttaggccc tagcggcaga 1260aaggaaaacc tgaagactga ggacaaagtg gaggagggcc gaggtgggct tcagtaagtc 1320cccggcggcg ctttagtttg agcgcatggc aagtcacatg cgtaaacgac actctctgga 1380agccctggag accctcgccc aactccacca gatagcagag gggtaagaga ggatgtgcaa 1440gcgacgacag atgctaaaat ccctggatca cgacgctgca gagcaccttt gcacaggatg 1500ctggcctttg ctcttactac actgaggaga gattcccgcg ggttccgcag gcagactaca 1560caggatgagg tggtggagtg gagtgagagc aattgtaacg gttaactgta acgttttctt 1620tcacacacac acacacacac acacacacac atgctaggat gcggaaatcc ccttatgact 1680tgctactttt tgattttgtg atattttgta ctttttagtt gttcagcaac tgtcttattt 1740aatggggaga ttttaagtaa cataactagt ggctctcagt taaaatgtga ggaagaacta 1800cagctcttaa atgtagcaat ggcactgttg caaactcagt gcaaacgcct agattgcttt 1860cttcttaacc tatttatttc tttgttaaat ttttctgatt gtttccttta tagagtgtct 1920cagggtgcag aggtcagact aagaaatatt ccaaatgtct tttagaagat agatgcactt 1980atgcagtaaa ttatcttggg atagttccca aaagattgct gaaaaagtag attgagtata 2040aaaacttgaa aatatatgat ggctcgtggg atgtcctact atcactgaac aaactaaagg 2100tgcactgctt tgggatttaa tttccagggt tgcttgatca ttatatcatt ggaacaactg 2160atacttcact actttaataa agaattaaca gagattgaac tccaagaggt gggtaatttg 2220gtttaaaaat acatgttcat gggtttacca ctaactcctg agaaatgtta aaggttcaca 2280ggggttccct tctctcaatg tttgtaataa ttgctcataa gcaataccag caattcataa 2340aaactgctta cttatgccat agaaaattaa acacaaagtg tatacatgta ttatgcttct 2400aaatgctcat tctaccagat acacatttaa aagagaaaaa aggaacagaa acaagtcatt 2460tgagagtgga gacttataag aaggagtaca tttgagttga atacacaaat ctttacttct 2520ctaccaattc ctattcccaa aatgaacata ttactgggga aagttagttg agaatcagag 2580catatgttat tggggaaagg atatgtttat tgacacataa tctgtaccag gtatgcatta 2640aaatatattt gttaatttaa tatttaaacc tgagagatag gtattgtttc ccagatgagg 2700acaatgaggc aaagaaatat caagtaactt gccaaaggtt acaagatatt cattccatgg 2760atgcacaaag aagtgcatct agttccacag ctgattatgg ttgtcttgct tttcttccca 2820ttgcaccagc ttgtcctcca aaatcatgaa tgatacacat gaagataact ttttttaaaa 2880aaaagcagaa atacacaatg atctcccttg taagctccta aggtggcttt tctttctcta 2940acttctagta aatataaacg gtttgtttga aaactatttt aaaatgtcaa caatatggag 3000aataaccccc cccaacacac ctataaaaac ccaaattttt ggaacaaaga taatggaacc 3060tccattttca aactgaagca cagggacaga aaatatattt ctagttatca cttaagcact 3120caatcattag aggctacaag aataatattt ttaaagttac agtattttac aattattaga 3180aaacattcta tataaaagaa gtcagttgat actttaaaat ctcccatttg gtttataaaa 3240tcccttaatt tgacctctat atcttaaatt ccaagatgtt taaatttgct agttgcatta 3300tactgggtca tgaaaaatta tcccttgaaa tagatatgaa acatgttact tcatttctgg 3360tttaaataac ttgtggaatc tttcctaatg acaacctgat attaagggaa actaaagaaa 3420atgttattgt ggatcccaca gtactatatt acactgtttt ttttgtttgt tttgttagtt 3480ttttttattt aaagcaaacc tcaaacatta ttgggtatca attaccacct ggttgtattg 3540aaatagtaac ttatcaatgc catgtaaaaa ttaattccat tttcgaagcc acctggcaga 3600caggtttagc tgtttcatca gcagcctaat atatactgtt aaatttgtta aggatttcac 3660tttgaaggat acatgcaaaa catatagtta ctattttcat gagtcctgct tctagctcca 3720ttgtggaata cagaaaatta aatatacctg ttaagttcgt atctaaacct aagacattac 3780caaggtttgt acaaattcta ctacctgaca tttattccaa gaagatctgg aaagttaaat 3840aaatttataa atttaataac aaaaaaaaaa aaaaaaaa 387885411DNAHomo sapiens 8gtgtcccata gtgtttccaa acttggaaag ggcgggggag ggcgggagga tgcggagggc 60ggaggtatgc agacaacgag tcagagtttc cccttgaaag cctcaaaagt gtccacgtcc 120tcaaaaagaa tggaaccaat ttaagaagcc agccccgtgg ccacgtccct tcccccattc 180gctccctcct ctgcgccccc gcaggctcct cccagctgtg gctgcccggg cccccagccc 240cagccctccc attggtggag gcccttttgg aggcacccta gggccaggga aacttttgcc 300gtataaatag ggcagatccg ggctttatta ttttagcacc acggcagcag gaggtttcgg 360ctaagttgga ggtactggcc acgactgcat gcccgcgccc gccaggtgat acctccgccg 420gtgacccagg ggctctgcga cacaaggagt ctgcatgtct aagtgctaga catgctcagc 480tttgtggata cgcggacttt gttgctgctt gcagtaacct tatgcctagc aacatgccaa 540tctttacaag aggaaactgt aagaaagggc ccagccggag atagaggacc acgtggagaa 600aggggtccac caggcccccc aggcagagat ggtgaagatg gtcccacagg ccctcctggt 660ccacctggtc ctcctggccc ccctggtctc ggtgggaact ttgctgctca gtatgatgga 720aaaggagttg gacttggccc tggaccaatg ggcttaatgg gacctagagg cccacctggt 780gcagctggag ccccaggccc tcaaggtttc caaggacctg ctggtgagcc tggtgaacct 840ggtcaaactg gtcctgcagg tgctcgtggt ccagctggcc ctcctggcaa ggctggtgaa 900gatggtcacc ctggaaaacc cggacgacct ggtgagagag gagttgttgg accacagggt 960gctcgtggtt tccctggaac tcctggactt cctggcttca aaggcattag gggacacaat 1020ggtctggatg gattgaaggg acagcccggt gctcctggtg tgaagggtga acctggtgcc 1080cctggtgaaa atggaactcc aggtcaaaca ggagcccgtg ggcttcctgg tgagagagga 1140cgtgttggtg cccctggccc agctggtgcc cgtggcagtg atggaagtgt gggtcccgtg 1200ggtcctgctg gtcccattgg gtctgctggc cctccaggct tcccaggtgc ccctggcccc 1260aagggtgaaa ttggagctgt tggtaacgct ggtcctgctg gtcccgccgg tccccgtggt 1320gaagtgggtc ttccaggcct ctccggcccc gttggacctc ctggtaatcc tggagcaaac 1380ggccttactg gtgccaaggg tgctgctggc cttcccggcg ttgctggggc tcccggcctc 1440cctggacccc gcggtattcc tggccctgtt ggtgctgccg gtgctactgg tgccagagga 1500cttgttggtg agcctggtcc agctggctcc aaaggagaga gcggtaacaa gggtgagccc 1560ggctctgctg ggccccaagg tcctcctggt cccagtggtg aagaaggaaa gagaggccct 1620aatggggaag ctggatctgc cggccctcca ggacctcctg ggctgagagg tagtcctggt 1680tctcgtggtc ttcctggagc tgatggcaga gctggcgtca tgggccctcc tggtagtcgt 1740ggtgcaagtg gccctgctgg agtccgagga cctaatggag atgctggtcg ccctggggag 1800cctggtctca tgggacccag aggtcttcct ggttcccctg gaaatatcgg ccccgctgga 1860aaagaaggtc ctgtcggcct ccctggcatc gacggcaggc ctggcccaat tggcccagct 1920ggagcaagag gagagcctgg caacattgga ttccctggac ccaaaggccc cactggtgat 1980cctggcaaaa acggtgataa aggtcatgct ggtcttgctg gtgctcgggg tgctccaggt 2040cctgatggaa acaatggtgc tcagggacct cctggaccac agggtgttca aggtggaaaa 2100ggtgaacagg gtccccctgg tcctccaggc ttccagggtc tgcctggccc ctcaggtccc 2160gctggtgaag ttggcaaacc aggagaaagg ggtctccatg gtgagtttgg tctccctggt 2220cctgctggtc caagagggga acgcggtccc ccaggtgaga gtggtgctgc cggtcctact 2280ggtcctattg gaagccgagg tccttctgga cccccagggc ctgatggaaa caagggtgaa 2340cctggtgtgg ttggtgctgt gggcactgct ggtccatctg gtcctagtgg actcccagga 2400gagaggggtg ctgctggcat acctggaggc aagggagaaa agggtgaacc tggtctcaga 2460ggtgaaattg gtaaccctgg cagagatggt gctcgtggtg ctcctggtgc tgtaggtgcc 2520cctggtcctg ctggagccac aggtgaccgg ggcgaagctg gggctgctgg tcctgctggt 2580cctgctggtc ctcggggaag ccctggtgaa cgtggtgagg tcggtcctgc tggccccaat 2640ggatttgctg gtcctgctgg tgctgctggt caacctggtg ctaaaggaga aagaggagcc 2700aaagggccta agggtgaaaa cggtgttgtt ggtcccacag gccccgttgg agctgctggc 2760ccagctggtc caaatggtcc ccccggtcct gctggaagtc gtggtgatgg aggcccccct 2820ggtatgactg gtttccctgg tgctgctgga cggactggtc ccccaggacc ctctggtatt 2880tctggccctc ctggtccccc tggtcctgct gggaaagaag ggcttcgtgg tcctcgtggt 2940gaccaaggtc cagttggccg aactggagaa gtaggtgcag ttggtccccc tggcttcgct 3000ggtgagaagg gtccctctgg agaggctggt actgctggac ctcctggcac tccaggtcct 3060cagggtcttc ttggtgctcc tggtattctg ggtctccctg gctcgagagg tgaacgtggt 3120ctaccaggtg ttgctggtgc tgtgggtgaa cctggtcctc ttggcattgc cggccctcct 3180ggggcccgtg gtcctcctgg tgctgtgggt agtcctggag tcaacggtgc tcctggtgaa 3240gctggtcgtg atggcaaccc tgggaacgat ggtcccccag gtcgcgatgg tcaacccgga 3300cacaagggag agcgcggtta ccctggcaat attggtcccg ttggtgctgc aggtgcacct 3360ggtcctcatg gccccgtggg tcctgctggc aaacatggaa accgtggtga aactggtcct 3420tctggtcctg ttggtcctgc tggtgctgtt ggcccaagag gtcctagtgg cccacaaggc 3480attcgtggcg ataagggaga gcccggtgaa aaggggccca gaggtcttcc tggcttaaag 3540ggacacaatg gattgcaagg tctgcctggt atcgctggtc accatggtga tcaaggtgct 3600cctggctccg tgggtcctgc tggtcctagg ggccctgctg gtccttctgg ccctgctgga 3660aaagatggtc gcactggaca tcctggtaca gttggacctg ctggcattcg aggccctcag 3720ggtcaccaag gccctgctgg cccccctggt ccccctggcc ctcctggacc tccaggtgta 3780agcggtggtg gttatgactt tggttacgat ggagacttct acagggctga ccagcctcgc 3840tcagcacctt ctctcagacc caaggactat gaagttgatg ctactctgaa gtctctcaac 3900aaccagattg agacccttct tactcctgaa ggctctagaa agaacccagc tcgcacatgc 3960cgtgacttga gactcagcca cccagagtgg agcagtggtt actactggat tgaccctaac 4020caaggatgca ctatggatgc tatcaaagta tactgtgatt tctctactgg cgaaacctgt 4080atccgggccc aacctgaaaa catcccagcc aagaactggt ataggagctc caaggacaag 4140aaacacgtct ggctaggaga aactatcaat gctggcagcc agtttgaata taatgtagaa 4200ggagtgactt ccaaggaaat ggctacccaa cttgccttca tgcgcctgct ggccaactat 4260gcctctcaga acatcaccta ccactgcaag aacagcattg catacatgga tgaggagact 4320ggcaacctga aaaaggctgt cattctacag ggctctaatg atgttgaact tgttgctgag 4380ggcaacagca ggttcactta cactgttctt gtagatggct gctctaaaaa gacaaatgaa 4440tggggaaaga caatcattga atacaaaaca aataagccat cacgcctgcc cttccttgat 4500attgcacctt tggacatcgg tggtgctgac caggaattct ttgtggacat tggcccagtc 4560tgtttcaaat aaatgaactc aatctaaatt aaaaaagaaa gaaatttgaa aaaactttct 4620ctttgccatt tcttcttctt cttttttaac tgaaagctga atccttccat ttcttctgca 4680catctacttg cttaaattgt gggcaaaaga gaaaaagaag gattgatcag agcattgtgc 4740aatacagttt cattaactcc ttcccccgct cccccaaaaa tttgaatttt tttttcaaca 4800ctcttacacc tgttatggaa aatgtcaacc tttgtaagaa aaccaaaata aaaattgaaa 4860aataaaaacc ataaacattt gcaccacttg tggcttttga atatcttcca cagagggaag 4920tttaaaaccc aaacttccaa aggtttaaac tacctcaaaa cactttccca tgagtgtgat 4980ccacattgtt aggtgctgac ctagacagag atgaactgag gtccttgttt tgttttgttc 5040ataatacaaa ggtgctaatt aatagtattt cagatacttg aagaatgttg atggtgctag 5100aagaatttga gaagaaatac tcctgtattg agttgtatcg tgtggtgtat tttttaaaaa 5160atttgattta gcattcatat tttccatctt attcccaatt aaaagtatgc agattatttg 5220cccaaatctt cttcagattc agcatttgtt ctttgccagt ctcattttca tcttcttcca 5280tggttccaca gaagctttgt ttcttgggca agcagaaaaa ttaaattgta cctattttgt 5340atatgtgaga tgtttaaata aattgtgaaa aaaatgaaat aaagcatgtt tggttttcca 5400aaagaacata t 541195490DNAHomo sapiens 9ggctgagttt tatgacgggc ccggtgctga agggcaggga acaacttgat ggtgctactt 60tgaactgctt ttcttttctc ctttttgcac aaagagtctc atgtctgata tttagacatg 120atgagctttg tgcaaaaggg gagctggcta cttctcgctc tgcttcatcc cactattatt 180ttggcacaac aggaagctgt tgaaggagga tgttcccatc ttggtcagtc ctatgcggat 240agagatgtct ggaagccaga accatgccaa atatgtgtct gtgactcagg atccgttctc 300tgcgatgaca taatatgtga cgatcaagaa ttagactgcc ccaacccaga aattccattt 360ggagaatgtt gtgcagtttg cccacagcct ccaactgctc ctactcgccc tcctaatggt 420caaggacctc aaggccccaa gggagatcca ggccctcctg gtattcctgg gagaaatggt 480gaccctggta ttccaggaca accagggtcc cctggttctc ctggcccccc tggaatctgt 540gaatcatgcc ctactggtcc tcagaactat tctccccagt atgattcata tgatgtcaag 600tctggagtag cagtaggagg actcgcaggc tatcctggac cagctggccc cccaggccct 660cccggtcccc ctggtacatc tggtcatcct ggttcccctg gatctccagg ataccaagga 720ccccctggtg aacctgggca agctggtcct tcaggccctc caggacctcc tggtgctata 780ggtccatctg gtcctgctgg aaaagatgga gaatcaggta gacccggacg acctggagag 840cgaggattgc ctggacctcc aggtatcaaa ggtccagctg ggatacctgg attccctggt 900atgaaaggac acagaggctt cgatggacga aatggagaaa agggtgaaac aggtgctcct 960ggattaaagg gtgaaaatgg tcttccaggc gaaaatggag ctcctggacc catgggtcca 1020agaggggctc ctggtgagcg aggacggcca ggacttcctg gggctgcagg tgctcggggt 1080aatgacggtg ctcgaggcag tgatggtcaa ccaggccctc ctggtcctcc tggaactgcc 1140ggattccctg gatcccctgg tgctaagggt gaagttggac ctgcagggtc tcctggttca 1200aatggtgccc ctggacaaag aggagaacct ggacctcagg gacacgctgg tgctcaaggt 1260cctcctggcc ctcctgggat taatggtagt cctggtggta aaggcgaaat gggtcccgct 1320ggcattcctg gagctcctgg actgatggga gcccggggtc ctccaggacc agccggtgct 1380aatggtgctc ctggactgcg aggtggtgca ggtgagcctg gtaagaatgg tgccaaagga 1440gagcccggac cacgtggtga acgcggtgag gctggtattc caggtgttcc aggagctaaa 1500ggcgaagatg gcaaggatgg atcacctgga gaacctggtg caaatgggct tccaggagct 1560gcaggagaaa ggggtgcccc tgggttccga ggacctgctg gaccaaatgg catcccagga 1620gaaaagggtc ctgctggaga gcgtggtgct ccaggccctg cagggcccag aggagctgct 1680ggagaacctg gcagagatgg cgtccctgga ggtccaggaa tgaggggcat gcccggaagt 1740ccaggaggac caggaagtga tgggaaacca gggcctcccg gaagtcaagg agaaagtggt 1800cgaccaggtc ctcctgggcc atctggtccc cgaggtcagc ctggtgtcat gggcttcccc 1860ggtcctaaag gaaatgatgg tgctcctggt aagaatggag aacgaggtgg ccctggagga 1920cctggccctc agggtcctcc tggaaagaat ggtgaaactg gacctcaggg acccccaggg 1980cctactgggc ctggtggtga caaaggagac acaggacccc ctggtccaca aggattacaa 2040ggcttgcctg gtacaggtgg tcctccagga gaaaatggaa aacctgggga accaggtcca 2100aagggtgatg ccggtgcacc tggagctcca ggaggcaagg gtgatgctgg tgcccctggt 2160gaacgtggac ctcctggatt ggcaggggcc ccaggactta gaggtggagc tggtccccct 2220ggtcccgaag gaggaaaggg tgctgctggt cctcctgggc cacctggtgc tgctggtact 2280cctggtctgc aaggaatgcc tggagaaaga ggaggtcttg gaagtcctgg tccaaagggt 2340gacaagggtg aaccaggcgg tccaggtgct gatggtgtcc cagggaaaga tggcccaagg 2400ggtcctactg gtcctattgg tcctcctggc ccagctggcc agcctggaga taagggtgaa 2460ggtggtgccc ccggacttcc aggtatagct ggacctcgtg gtagccctgg tgagagaggt 2520gaaactggcc ctccaggacc tgctggtttc cctggtgctc ctggacagaa tggtgaacct 2580ggtggtaaag gagaaagagg ggctccgggt gagaaaggtg aaggaggccc tcctggagtt 2640gcaggacccc ctggaggttc tggacctgct ggtcctcctg gtccccaagg tgtcaaaggt 2700gaacgtggca gtcctggtgg acctggtgct gctggcttcc ctggtgctcg tggtcttcct 2760ggtcctcctg gtagtaatgg taacccagga cccccaggtc ccagcggttc tccaggcaag 2820gatgggcccc caggtcctgc gggtaacact ggtgctcctg gcagccctgg agtgtctgga 2880ccaaaaggtg atgctggcca accaggagag aagggatcgc ctggtgccca gggcccacca 2940ggagctccag gcccacttgg gattgctggg atcactggag cacggggtct tgcaggacca

3000ccaggcatgc caggtcctag gggaagccct ggccctcagg gtgtcaaggg tgaaagtggg 3060aaaccaggag ctaacggtct cagtggagaa cgtggtcccc ctggacccca gggtcttcct 3120ggtctggctg gtacagctgg tgaacctgga agagatggaa accctggatc agatggtctt 3180ccaggccgag atggatctcc tggtggcaag ggtgatcgtg gtgaaaatgg ctctcctggt 3240gcccctggcg ctcctggtca tccaggccca cctggtcctg tcggtccagc tggaaagagt 3300ggtgacagag gagaaagtgg ccctgctggc cctgctggtg ctcccggtcc tgctggttcc 3360cgaggtgctc ctggtcctca aggcccacgt ggtgacaaag gtgaaacagg tgaacgtgga 3420gctgctggca tcaaaggaca tcgaggattc cctggtaatc caggtgcccc aggttctcca 3480ggccctgctg gtcagcaggg tgcaatcggc agtccaggac ctgcaggccc cagaggacct 3540gttggaccca gtggacctcc tggcaaagat ggaaccagtg gacatccagg tcccattgga 3600ccaccagggc ctcgaggtaa cagaggtgaa agaggatctg agggctcccc aggccaccca 3660gggcaaccag gccctcctgg acctcctggt gcccctggtc cttgctgtgg tggtgttgga 3720gccgctgcca ttgctgggat tggaggtgaa aaagctggcg gttttgcccc gtattatgga 3780gatgaaccaa tggatttcaa aatcaacacc gatgagatta tgacttcact caagtctgtt 3840aatggacaaa tagaaagcct cattagtcct gatggttctc gtaaaaaccc cgctagaaac 3900tgcagagacc tgaaattctg ccatcctgaa ctcaagagtg gagaatactg ggttgaccct 3960aaccaaggat gcaaattgga tgctatcaag gtattctgta atatggaaac tggggaaaca 4020tgcataagtg ccaatccttt gaatgttcca cggaaacact ggtggacaga ttctagtgct 4080gagaagaaac acgtttggtt tggagagtcc atggatggtg gttttcagtt tagctacggc 4140aatcctgaac ttcctgaaga tgtccttgat gtgcagctgg cattccttcg acttctctcc 4200agccgagctt cccagaacat cacatatcac tgcaaaaata gcattgcata catggatcag 4260gccagtggaa atgtaaagaa ggccctgaag ctgatggggt caaatgaagg tgaattcaag 4320gctgaaggaa atagcaaatt cacctacaca gttctggagg atggttgcac gaaacacact 4380ggggaatgga gcaaaacagt ctttgaatat cgaacacgca aggctgtgag actacctatt 4440gtagatattg caccctatga cattggtggt cctgatcaag aatttggtgt ggacgttggc 4500cctgtttgct ttttataaac caaactctat ctgaaatccc aacaaaaaaa atttaactcc 4560atatgtgttc ctcttgttct aatcttgtca accagtgcaa gtgaccgaca aaattccagt 4620tatttatttc caaaatgttt ggaaacagta taatttgaca aagaaaaatg atacttctct 4680ttttttgctg ttccaccaaa tacaattcaa atgctttttg ttttattttt ttaccaattc 4740caatttcaaa atgtctcaat ggtgctataa taaataaact tcaacactct ttatgataac 4800aacactgtgt tatattcttt gaatcctagc ccatctgcag agcaatgact gtgctcacca 4860gtaaaagata acctttcttt ctgaaatagt caaatacgaa attagaaaag ccctccctat 4920tttaactacc tcaactggtc agaaacacag attgtattct atgagtccca gaagatgaaa 4980aaaattttat acgttgataa aacttataaa tttcattgat taatctcctg gaagattggt 5040ttaaaaagaa aagtgtaatg caagaattta aagaaatatt tttaaagcca caattatttt 5100aatattggat atcaactgct tgtaaaggtg ctcctctttt ttcttgtcat tgctggtcaa 5160gattactaat atttgggaag gctttaaaga cgcatgttat ggtgctaatg tactttcact 5220tttaaactct agatcagaat tgttgacttg cattcagaac ataaatgcac aaaatctgta 5280catgtctccc atcagaaaga ttcattggca tgccacaggg gattctcctc cttcatcctg 5340taaaggtcaa caataaaaac caaattatgg ggctgctttt gtcacactag catagagaat 5400gtgttgaaat ttaactttgt aagcttgtat gtggttgttg atcttttttt tccttacaga 5460cacccataat aaaatatcat attaaaattc 5490109169DNAHomo sapiens 10gatgacgctg cggcttctgg tggccgcgct ctgcgccggg atcctggcag aggcgccccg 60agtgcgagcc cagcacaggg agagagtgac ctgcacgcgc ctttacgccg ctgacattgt 120gttcttactg gatggctcct catccattgg ccgcagcaat ttccgcgagg tccgcagctt 180tctcgaaggg ctggtgctgc ctttctctgg agcagccagt gcacagggtg tgcgctttgc 240cacagtgcag tacagcgatg acccacggac agagttcggc ctggatgcac ttggctctgg 300gggtgatgtg atccgcgcca tccgtgagct tagctacaag gggggcaaca ctcgcacagg 360ggctgcaatt ctccatgtgg ctgaccatgt cttcctgccc cagctggccc gacctggtgt 420ccccaaggtc tgcatcctga tcacagacgg gaagtcccag gacctggtgg acacagctgc 480ccaaaggctg aaggggcagg gggtcaagct atttgctgtg gggatcaaga atgctgaccc 540tgaggagctg aagcgagttg cctcacagcc caccagtgac ttcttcttct tcgtcaatga 600cttcagcatc ttgaggacac tactgcccct cgtttcccgg agagtgtgca cgactgctgg 660tggcgtgcct gtgacccgac ctccggatga ctcgacctct gctccacgag acctggtgct 720gtctgagcca agcagccaat ccttgagagt acagtggaca gcggccagtg gccctgtgac 780tggctacaag gtccagtaca ctcctctgac ggggctggga cagccactgc cgagtgagcg 840gcaggaggtg aacgtcccag ctggtgagac cagtgtgcgg ctgcggggtc tccggccact 900gaccgagtac caagtgactg tgattgccct ctacgccaac agcatcgggg aggctgtgag 960cgggacagct cggaccactg ccctagaagg gccggaactg accatccaga ataccacagc 1020ccacagcctc ctggtggcct ggcggagtgt gccaggtgcc actggctacc gtgtgacatg 1080gcgggtcctc agtggtgggc ccacacagca gcaggagctg ggccctgggc agggttcagt 1140gttgctgcgt gacttggagc ctggcacgga ctatgaggtg accgtgagca ccctatttgg 1200ccgcagtgtg gggcccgcca cttccctgat ggctcgcact gacgcttctg ttgagcagac 1260cctgcgcccg gtcatcctgg gccccacatc catcctcctt tcctggaact tggtgcctga 1320ggcccgtggc taccggttgg aatggcggcg tgagactggc ttggagccac cgcagaaggt 1380ggtactgccc tctgatgtga cccgctacca gttggatggg ctgcagccgg gcactgagta 1440ccgcctcaca ctctacactc tgctggaggg ccacgaggtg gccacccctg caaccgtggt 1500tcccactgga ccagagctgc ctgtgagccc tgtaacagac ctgcaagcca ccgagctgcc 1560cgggcagcgg gtgcgagtgt cctggagccc agtccctggt gccacccagt accgcatcat 1620tgtgcgcagc acccaggggg ttgagcggac cctggtgctt cctgggagtc agacagcatt 1680cgacttggat gacgttcagg ctgggcttag ctacactgtg cgggtgtctg ctcgagtggg 1740tccccgtgag ggcagtgcca gtgtcctcac tgtccgccgg gagccggaaa ctccacttgc 1800tgttccaggg ctgcgggttg tggtgtcaga tgcaacgcga gtgagggtgg cctggggacc 1860cgtccctgga gccagtggat ttcggattag ctggagcaca ggcagtggtc cggagtccag 1920ccagacactg cccccagact ctactgccac agacatcaca gggctgcagc ctggaaccac 1980ctaccaggtg gctgtgtcgg tactgcgagg cagagaggag ggccctgctg cagtcatcgt 2040ggctcgaacg gacccactgg gcccagtgag gacggtccat gtgactcagg ccagcagctc 2100atctgtcacc attacctgga ccagggttcc tggcgccaca ggatacaggg tttcctggca 2160ctcagcccac ggcccagaga aatcccagtt ggtttctggg gaggccacgg tggctgagct 2220ggatggactg gagccagata ctgagtatac ggtgcatgtg agggcccatg tggctggcgt 2280ggatgggccc cctgcctctg tggttgtgag gactgcccct gagcctgtgg gtcgtgtgtc 2340gaggctgcag atcctcaatg cttccagcga cgttctacgg atcacctggg taggggtcac 2400tggagccaca gcttacagac tggcctgggg ccggagtgaa ggcggcccca tgaggcacca 2460gatactccca ggaaacacag actctgcaga gatccggggt ctcgaaggtg gagtcagcta 2520ctcagtgcga gtgactgcac ttgtcgggga ccgcgagggc acacctgtct ccattgttgt 2580cactacgccg cctgaggctc cgccagccct ggggacgctt cacgtggtgc agcgcgggga 2640gcactcgctg aggctgcgct gggagccggt gcccagagcg cagggcttcc ttctgcactg 2700gcaacctgag ggtggccagg aacagtcccg ggtcctgggg cccgagctca gcagctatca 2760cctggacggg ctggagccag cgacacagta ccgcgtgagg ctgagtgtcc tagggccagc 2820tggagaaggg ccctctgcag aggtgactgc gcgcactgag tcacctcgtg ttccaagcat 2880tgaactacgt gtggtggaca cctcgatcga ctcggtgact ttggcctgga ctccagtgtc 2940cagggcatcc agctacatcc tatcctggcg gccactcaga ggccctggcc aggaagtgcc 3000tgggtccccg cagacacttc cagggatctc aagctcccag cgggtgacag ggctagagcc 3060tggcgtctct tacatcttct ccctgacgcc tgtcctggat ggtgtgcggg gtcctgaggc 3120atctgtcaca cagacgccag tgtgcccccg tggcctggcg gatgtggtgt tcctaccaca 3180tgccactcaa gacaatgctc accgtgcgga ggctacgagg agggtcctgg agcgtctggt 3240gttggcactt gggcctcttg ggccacaggc agttcaggtt ggcctgctgt cttacagtca 3300tcggccctcc ccactgttcc cactgaatgg ctcccatgac cttggcatta tcttgcaaag 3360gatccgtgac atgccctaca tggacccaag tgggaacaac ctgggcacag ccgtggtcac 3420agctcacaga tacatgttgg caccagatgc tcctgggcgc cgccagcacg taccaggggt 3480gatggttctg ctagtggatg aacccttgag aggtgacata ttcagcccca tccgtgaggc 3540ccaggcttct gggcttaatg tggtgatgtt gggaatggct ggagcggacc cagagcagct 3600gcgtcgcttg gcgccgggta tggactctgt ccagaccttc ttcgccgtgg atgatgggcc 3660aagcctggac caggcagtca gtggtctggc cacagccctg tgtcaggcat ccttcactac 3720tcagccccgg ccagagccct gcccagtgta ttgtccaaag ggccagaagg gggaacctgg 3780agagatgggc ctgagaggac aagttgggcc tcctggcgac cctggcctcc cgggcaggac 3840cggtgctccc ggcccccagg ggccccctgg aagtgccact gccaagggcg agaggggctt 3900ccctggagca gatgggcgtc caggcagccc tggccgcgcc gggaatcctg ggacccctgg 3960agcccctggc ctaaagggct ctccagggtt gcctggccct cgtggggacc cgggagagcg 4020aggacctcga ggcccaaagg gggagccggg ggctcccgga caagtcatcg gaggtgaagg 4080acctgggctt cctgggcgga aaggggaccc tggaccatcg ggcccccctg gacctcgtgg 4140accactgggg gacccaggac cccgtggccc cccagggctt cctggaacag ccatgaaggg 4200tgacaaaggc gatcgtgggg agcggggtcc ccctggacca ggtgaaggtg gcattgctcc 4260tggggagcct gggctgccgg gtcttcccgg aagccctgga ccccaaggcc ccgttggccc 4320ccctggaaag aaaggagaaa aaggtgactc tgaggatgga gctccaggcc tcccaggaca 4380acctgggtct ccgggtgagc agggcccacg gggacctcct ggagctattg gccccaaagg 4440tgaccggggc tttccagggc ccctgggtga ggctggagag aagggcgaac gtggaccccc 4500aggcccagcg ggatcccggg ggctgccagg ggttgctgga cgtcctggag ccaagggtcc 4560tgaagggcca ccaggaccca ctggccgcca aggagagaag ggggagcctg gtcgccctgg 4620ggaccctgca gtggtgggac ctgctgttgc tggacccaaa ggagaaaagg gagatgtggg 4680gcccgctggg cccagaggag ctaccggagt ccaaggggaa cggggcccac ccggcttggt 4740tcttcctgga gaccctggcc ccaagggaga ccctggagac cggggtccca ttggccttac 4800tggcagagca ggacccccag gtgactcagg gcctcctgga gagaagggag accctgggcg 4860gcctggcccc ccaggacctg ttggcccccg aggacgagat ggtgaagttg gagagaaagg 4920tgacgagggt cctccgggtg acccgggttt gcctggaaaa gcaggcgagc gtggccttcg 4980gggggcacct ggagttcggg ggcctgtggg tgaaaaggga gaccagggag atcctggaga 5040ggatggacga aatggcagcc ctggatcatc tggacccaag ggtgaccgtg gggagccggg 5100tcccccagga cccccgggac ggctggtaga cacaggacct ggagccagag agaagggaga 5160gcctggggac cgcggacaag agggtcctcg agggcccaag ggtgatcctg gcctccctgg 5220agcccctggg gaaaggggca ttgaagggtt tcggggaccc ccaggcccac agggggaccc 5280aggtgtccga ggcccagcag gagaaaaggg tgaccggggt ccccctgggc tggatggccg 5340gagcggactg gatgggaaac caggagccgc tgggccctct gggccgaatg gtgctgcagg 5400caaagctggg gacccaggga gagacgggct tccaggcctc cgtggagaac agggcctccc 5460tggcccctct ggtccccctg gattaccggg aaagccaggc gaggatggca aacctggcct 5520gaatggaaaa aacggagaac ctggggaccc tggagaagac gggaggaagg gagagaaagg 5580agattcaggc gcctctggga gagaaggtcg tgatggcccc aagggtgagc gtggagctcc 5640tggtatcctt ggaccccagg ggcctccagg cctcccaggg ccagtgggcc ctcctggcca 5700gggttttcct ggtgtcccag gaggcacggg ccccaagggt gaccgtgggg agactggatc 5760caaaggggag cagggcctcc ctggagagcg tggcctgcga ggagagcctg gaagtgtgcc 5820gaatgtggat cggttgctgg aaactgctgg catcaaggca tctgccctgc gggagatcgt 5880ggagacctgg gatgagagct ctggtagctt cctgcctgtg cccgaacggc gtcgaggccc 5940caagggggac tcaggcgaac agggcccccc aggcaaggag ggccccatcg gctttcctgg 6000agaacgcggg ctgaagggcg accgtggaga ccctggccct caggggccac ctggtctggc 6060ccttggggag aggggccccc ccgggccttc cggccttgcc ggggagcctg gaaagcctgg 6120tattcccggg ctcccaggca gggctggggg tgtgggagag gcaggaaggc caggagagag 6180gggagaacgg ggagagaaag gagaacgtgg agaacagggc agagatggcc ctcctggact 6240ccctggaacc cctgggcccc ccggaccccc tggccccaag gtgtctgtgg atgagccagg 6300tcctggactc tctggagaac agggaccccc tggactcaag ggtgctaagg gggagccggg 6360cagcaatggt gaccaaggtc ccaaaggaga caggggtgtg ccaggcatca aaggagaccg 6420gggagagcct ggaccgaggg gtcaggacgg caacccgggt ctaccaggag agcgtggtat 6480ggctgggcct gaagggaagc cgggtctgca gggtccaaga ggcccccctg gcccagtggg 6540tggtcatgga gaccctggac cacctggtgc cccgggtctt gctggccctg caggacccca 6600aggaccttct ggcctgaagg gggagcctgg agagacagga cctccaggac ggggcctgac 6660tggacctact ggagctgtgg gacttcctgg accccccggc ccttcaggcc ttgtgggtcc 6720acaggggtct ccaggtttgc ctggacaagt gggggagaca gggaagccgg gagccccagg 6780tcgagatggt gccagtggaa aagatggaga cagagggagc cctggtgtgc cagggtcacc 6840aggtctgcct ggccctgtcg gacctaaagg agaacctggc cccacggggg cccctggaca 6900ggctgtggtc gggctccctg gagcaaaggg agagaaggga gcccctggag gccttgctgg 6960agacctggtg ggtgagccgg gagccaaagg tgaccgagga ctgccagggc cgcgaggcga 7020gaagggtgaa gctggccgtg caggggagcc cggagaccct ggggaagatg gtcagaaagg 7080ggctccagga cccaaaggtt tcaagggtga cccaggagtc ggggtcccgg gctcccctgg 7140gcctcctggc cctccaggtg tgaagggaga tctgggcctc cctggcctgc ccggtgctcc 7200tggtgttgtt gggttcccgg gtcagacagg ccctcgagga gagatgggtc agccaggccc 7260tagtggagag cggggtctgg caggcccccc agggagagaa ggaatcccag gacccctggg 7320gccacctgga ccaccggggt cagtgggacc acctggggcc tctggactca aaggagacaa 7380gggagaccct ggagtagggc tgcctgggcc ccgaggcgag cgtggggagc caggcatccg 7440gggtgaagat ggccgccccg gccaggaggg accccgagga ctcacggggc cccctggcag 7500caggggagag cgtggggaga agggtgatgt tgggagtgca ggactaaagg gtgacaaggg 7560agactcagct gtgatcctgg ggcctccagg cccacggggt gccaaggggg acatgggtga 7620acgagggcct cggggcttgg atggtgacaa aggacctcgg ggagacaatg gggaccctgg 7680tgacaagggc agcaagggag agcctggtga caagggctca gccgggttgc caggactgcg 7740tggactcctg ggaccccagg gtcaacctgg tgcagcaggg atccctggtg acccgggatc 7800cccaggaaag gatggagtgc ctggtatccg aggagaaaaa ggagatgttg gcttcatggg 7860tccccggggc ctcaagggtg aacggggagt gaagggagcc tgtggccttg atggagagaa 7920gggagacaag ggagaagctg gtcccccagg ccgccccggg ctggcaggac acaaaggaga 7980gatgggggag cctggtgtgc cgggccagtc gggggcccct ggcaaggagg gcctgatcgg 8040tcccaagggt gaccgaggct ttgacgggca gccaggcccc aagggtgacc agggcgagaa 8100aggggagcgg ggaaccccag gaattggggg cttcccaggc cccagtggaa atgatggctc 8160tgctggtccc ccagggccac ctggcagtgt tggtcccaga ggccccgaag gacttcaggg 8220ccagaagggt gagcgaggtc cccccggaga gagagtggtg ggggctcctg gggtccctgg 8280agctcctggc gagagagggg agcaggggcg gccagggcct gccggtcctc gaggcgagaa 8340gggagaagct gcactgacgg aggatgacat ccggggcttt gtgcgccaag agatgagtca 8400gcactgtgcc tgccagggcc agttcatcgc atctggatca cgacccctcc ctagttatgc 8460tgcagacact gccggctccc agctccatgc tgtgcctgtg ctccgcgtct ctcatgcaga 8520ggaggaagag cgggtacccc ctgaggatga tgagtactct gaatactccg agtattctgt 8580ggaggagtac caggaccctg aagctccttg ggatagtgat gacccctgtt ccctgccact 8640ggatgagggc tcctgcactg cctacaccct gcgctggtac catcgggctg tgacaggcag 8700cacagaggcc tgtcaccctt ttgtctatgg tggctgtgga gggaatgcca accgttttgg 8760gacccgtgag gcctgcgagc gccgctgccc accccgggtg gtccagagcc aggggacagg 8820tactgcccag gactgaggcc cagataatga gctgagattc agcatcccct ggaggagtcg 8880gggtctcagc agaaccccac tgtccctccc cttggtgcta gaggcttgtg tgcacgtgag 8940cgtgcgtgtg cacgtccgtt atttcagtga cttggtcccg tgggtctagc cttcccccct 9000gtggacaaac ccccattgtg gctcctgcca ccctggcaga tgactcactg tgggggggtg 9060gctgtgggca gtgagcggat gtgactggcg tctgacccgc cccttgaccc aagcctgtga 9120tgacatggtg ctgattctgg ggggcattaa agctgctgtt ttaaaaggc 9169112358DNAHomo sapiens 11aaactcacac aacaactctt ccccgctgag aggagacagc cagtgcgact ccaccctcca 60gctcgacggc agccgccccg gccgacagcc ccgagacgac agcccggcgc gtcccggtcc 120ccacctccga ccaccgccag cgctccaggc cccgccgctc cccgctcgcc gccaccgcgc 180cctccgctcc gcccgcagtg ccaaccatga ccgccgccag tatgggcccc gtccgcgtcg 240ccttcgtggt cctcctcgcc ctctgcagcc ggccggccgt cggccagaac tgcagcgggc 300cgtgccggtg cccggacgag ccggcgccgc gctgcccggc gggcgtgagc ctcgtgctgg 360acggctgcgg ctgctgccgc gtctgcgcca agcagctggg cgagctgtgc accgagcgcg 420acccctgcga cccgcacaag ggcctcttct gtgacttcgg ctccccggcc aaccgcaaga 480tcggcgtgtg caccgccaaa gatggtgctc cctgcatctt cggtggtacg gtgtaccgca 540gcggagagtc cttccagagc agctgcaagt accagtgcac gtgcctggac ggggcggtgg 600gctgcatgcc cctgtgcagc atggacgttc gtctgcccag ccctgactgc cccttcccga 660ggagggtcaa gctgcccggg aaatgctgcg aggagtgggt gtgtgacgag cccaaggacc 720aaaccgtggt tgggcctgcc ctcgcggctt accgactgga agacacgttt ggcccagacc 780caactatgat tagagccaac tgcctggtcc agaccacaga gtggagcgcc tgttccaaga 840cctgtgggat gggcatctcc acccgggtta ccaatgacaa cgcctcctgc aggctagaga 900agcagagccg cctgtgcatg gtcaggcctt gcgaagctga cctggaagag aacattaaga 960agggcaaaaa gtgcatccgt actcccaaaa tctccaagcc tatcaagttt gagctttctg 1020gctgcaccag catgaagaca taccgagcta aattctgtgg agtatgtacc gacggccgat 1080gctgcacccc ccacagaacc accaccctgc cggtggagtt caagtgccct gacggcgagg 1140tcatgaagaa gaacatgatg ttcatcaaga cctgtgcctg ccattacaac tgtcccggag 1200acaatgacat ctttgaatcg ctgtactaca ggaagatgta cggagacatg gcatgaagcc 1260agagagtgag agacattaac tcattagact ggaacttgaa ctgattcaca tctcattttt 1320ccgtaaaaat gatttcagta gcacaagtta tttaaatctg tttttctaac tgggggaaaa 1380gattcccacc caattcaaaa cattgtgcca tgtcaaacaa atagtctatc aaccccagac 1440actggtttga agaatgttaa gacttgacag tggaactaca ttagtacaca gcaccagaat 1500gtatattaag gtgtggcttt aggagcagtg ggagggtacc agcagaaagg ttagtatcat 1560cagatagcat cttatacgag taatatgcct gctatttgaa gtgtaattga gaaggaaaat 1620tttagcgtgc tcactgacct gcctgtagcc ccagtgacag ctaggatgtg cattctccag 1680ccatcaagag actgagtcaa gttgttcctt aagtcagaac agcagactca gctctgacat 1740tctgattcga atgacactgt tcaggaatcg gaatcctgtc gattagactg gacagcttgt 1800ggcaagtgaa tttgcctgta acaagccaga ttttttaaaa tttatattgt aaatattgtg 1860tgtgtgtgtg tgtgtgtata tatatatata tgtacagtta tctaagttaa tttaaagttg 1920tttgtgcctt tttatttttg tttttaatgc tttgatattt caatgttagc ctcaatttct 1980gaacaccata ggtagaatgt aaagcttgtc tgatcgttca aagcatgaaa tggatactta 2040tatggaaatt ctgctcagat agaatgacag tccgtcaaaa cagattgttt gcaaagggga 2100ggcatcagtg tccttggcag gctgatttct aggtaggaaa tgtggtagcc tcacttttaa 2160tgaacaaatg gcctttatta aaaactgagt gactctatat agctgatcag ttttttcacc 2220tggaagcatt tgtttctact ttgatatgac tgtttttcgg acagtttatt tgttgagagt 2280gtgaccaaaa gttacatgtt tgcacctttc tagttgaaaa taaagtgtat attttttcta 2340taaaaaaaaa aaaaaaaa 2358123256DNAHomo sapiens 12aggatacagc ggcttctgcg cgacttataa gagctccttg tgcggcgcca ttttaagcct 60ctcggtctgt ggcagcagcg ttggcccggc cccgggagcg gagagcgagg ggaggcggag 120acggaggaag gtctgaggag cagcttcagt ccccgccgag ccgccaccgc aggtcgagga 180cggtcggact cccgcggcgg gaggagcctg ttcccctgag ggtatttgaa gtataccata 240caactgtttt gaaaatccag cgtggacaat ggctactcaa gctgatttga tggagttgga 300catggccatg gaaccagaca gaaaagcggc tgttagtcac tggcagcaac agtcttacct 360ggactctgga atccattctg gtgccactac cacagctcct tctctgagtg gtaaaggcaa 420tcctgaggaa gaggatgtgg atacctccca agtcctgtat gagtgggaac agggattttc 480tcagtccttc actcaagaac aagtagctga tattgatgga cagtatgcaa tgactcgagc 540tcagagggta cgagctgcta tgttccctga gacattagat gagggcatgc agatcccatc 600tacacagttt gatgctgctc atcccactaa tgtccagcgt ttggctgaac catcacagat 660gctgaaacat gcagttgtaa acttgattaa ctatcaagat gatgcagaac ttgccacacg 720tgcaatccct gaactgacaa aactgctaaa tgacgaggac caggtggtgg ttaataaggc 780tgcagttatg gtccatcagc tttctaaaaa ggaagcttcc agacacgcta tcatgcgttc 840tcctcagatg gtgtctgcta ttgtacgtac catgcagaat acaaatgatg tagaaacagc

900tcgttgtacc gctgggacct tgcataacct ttcccatcat cgtgagggct tactggccat 960ctttaagtct ggaggcattc ctgccctggt gaaaatgctt ggttcaccag tggattctgt 1020gttgttttat gccattacaa ctctccacaa ccttttatta catcaagaag gagctaaaat 1080ggcagtgcgt ttagctggtg ggctgcagaa aatggttgcc ttgctcaaca aaacaaatgt 1140taaattcttg gctattacga cagactgcct tcaaatttta gcttatggca accaagaaag 1200caagctcatc atactggcta gtggtggacc ccaagcttta gtaaatataa tgaggaccta 1260tacttacgaa aaactactgt ggaccacaag cagagtgctg aaggtgctat ctgtctgctc 1320tagtaataag ccggctattg tagaagctgg tggaatgcaa gctttaggac ttcacctgac 1380agatccaagt caacgtcttg ttcagaactg tctttggact ctcaggaatc tttcagatgc 1440tgcaactaaa caggaaggga tggaaggtct ccttgggact cttgttcagc ttctgggttc 1500agatgatata aatgtggtca cctgtgcagc tggaattctt tctaacctca cttgcaataa 1560ttataagaac aagatgatgg tctgccaagt gggtggtata gaggctcttg tgcgtactgt 1620ccttcgggct ggtgacaggg aagacatcac tgagcctgcc atctgtgctc ttcgtcatct 1680gaccagccga caccaagaag cagagatggc ccagaatgca gttcgccttc actatggact 1740accagttgtg gttaagctct tacacccacc atcccactgg cctctgataa aggctactgt 1800tggattgatt cgaaatcttg ccctttgtcc cgcaaatcat gcacctttgc gtgagcaggg 1860tgccattcca cgactagttc agttgcttgt tcgtgcacat caggataccc agcgccgtac 1920gtccatgggt gggacacagc agcaatttgt ggagggggtc cgcatggaag aaatagttga 1980aggttgtacc ggagcccttc acatcctagc tcgggatgtt cacaaccgaa ttgttatcag 2040aggactaaat accattccat tgtttgtgca gctgctttat tctcccattg aaaacatcca 2100aagagtagct gcaggggtcc tctgtgaact tgctcaggac aaggaagctg cagaagctat 2160tgaagctgag ggagccacag ctcctctgac agagttactt cactctagga atgaaggtgt 2220ggcgacatat gcagctgctg ttttgttccg aatgtctgag gacaagccac aagattacaa 2280gaaacggctt tcagttgagc tgaccagctc tctcttcaga acagagccaa tggcttggaa 2340tgagactgct gatcttggac ttgatattgg tgcccaggga gaaccccttg gatatcgcca 2400ggatgatcct agctatcgtt cttttcactc tggtggatat ggccaggatg ccttgggtat 2460ggaccccatg atggaacatg agatgggtgg ccaccaccct ggtgctgact atccagttga 2520tgggctgcca gatctggggc atgcccagga cctcatggat gggctgcctc caggtgacag 2580caatcagctg gcctggtttg atactgacct gtaaatcatc ctttaggagt aacaatacaa 2640atggattttg ggagtgactc aagaagtgaa gaatgcacaa gaatggatca caagatggaa 2700tttatcaaac cctagccttg cttgttaaat tttttttttt ttttttttaa gaatatctgt 2760aatggtactg actttgcttg ctttgaagta gctctttttt tttttttttt tttttttttg 2820cagtaactgt tttttaagtc tctcgtagtg ttaagttata gtgaatactg ctacagcaat 2880ttctaatttt taagaattga gtaatggtgt agaacactaa ttcataatca ctctaattaa 2940ttgtaatctg aataaagtgt aacaattgtg tagccttttt gtataaaata gacaaataga 3000aaatggtcca attagtttcc tttttaatat gcttaaaata agcaggtgga tctatttcat 3060gtttttgatc aaaaactatt tgggatatgt atgggtaggg taaatcagta agaggtgtta 3120tttggaacct tgttttggac agtttaccag ttgcctttta tcccaaagtt gttgtaacct 3180gctgtgatac gatgcttcaa gagaaaatgc ggttataaaa aatggttcag aattaaactt 3240ttaattcatt cgattg 3256131424DNAHomo sapiens 13agcagtcagc cggccggaga cagagacttc acgactccca gtctcctcct cgccgcggcc 60gccgcctcct ccttctctcc tcctcctctt cctcctcctc cctcgctccc acagccatgt 120ctgcttagac cagagcagcc ccacagccaa ctagggcagc tgccgccgcc acaacagcaa 180ggacagccgc tgccgccgcc cgtgagcgat gacaggagtg tttgacagaa gggtccccag 240catccgatcc ggcgacttcc aagctccgtt ccagacgtcc gcagctatgc accatccgtc 300tcaggaatcg ccaactttgc ccgagtcttc agctaccgat tctgactact acagccctac 360ggggggagcc ccgcacggct actgctctcc tacctcggct tcctatggca aagctctcaa 420cccctaccag tatcagtatc acggcgtgaa cggctccgcc gggagctacc cagccaaagc 480ttatgccgac tatagctacg ctagctccta ccaccagtac ggcggcgcct acaaccgcgt 540cccaagcgcc accaaccagc cagagaaaga agtgaccgag cccgaggtga gaatggtgaa 600tggcaaacca aagaaagttc gtaaacccag gactatttat tccagctttc agctggccgc 660attacagaga aggtttcaga agactcagta cctcgccttg ccggaacgcg ccgagctggc 720cgcctcgctg ggattgacac aaacacaggt gaaaatctgg tttcagaaca aaagatccaa 780gatcaagaag atcatgaaaa acggggagat gcccccggag cacagtccca gctccagcga 840cccaatggcg tgtaactcgc cgcagtctcc agcggtgtgg gagccccagg gctcgtcccg 900ctcgctcagc caccaccctc atgcccaccc tccgacctcc aaccagtccc cagcgtccag 960ctacctggag aactctgcat cctggtacac aagtgcagcc agctcaatca attcccacct 1020gccgccgccg ggctccttac agcacccgct ggcgctggcc tccgggacac tctattagat 1080gggctgctct ctcttactct cttttttggg actactgtgt tttgctgttc tagaaaatca 1140taaagaaagg aattcatatg gggaagttcg gaaaactgaa aaagattcat gtgtaaagct 1200tttttttgca tgtaagttat tgcatttcaa aagacccccc ctttttttac agaggacttt 1260ttttgcgcaa ctgtggacac tttcaatggt gccttgaaat ctatgacctc aacttttcaa 1320aagacttttt tcaatgttat tttagccatg taaataagtg tagatagagg aattaaactg 1380tatattctgg ataaataaaa ttatttcgac catgaaaagc ggaa 1424142109DNAHomo sapiens 14ggagctgttt acccccactc taataggggt tcaatataaa aagccggcag agagctgtcc 60aagtcagacg cgcctctgca tctgcgccag gcgaacgggt cctgcgcctc ctgcagtccc 120agctctccac cgccgcgtgc gcctgcagac gctccgctcg ctgccttctc tcctggcagg 180cgctgccttt tctccccgtt aaaagggcac ttgggctgaa ggatcgcttt gagatctgag 240gaacccgcag cgctttgagg gacctgaagc tgtttttctt cgttttcctt tgggttcagt 300ttgaacggga ggtttttgat cccttttttt cagaatggat tatttgctca tgattttctc 360tctgctgttt gtggcttgcc aaggagctcc agaaacagtc ttaggcgctg agctcagcgc 420ggtgggtgag aacggcgggg agaaacccac tcccagtcca ccctggcggc tccgccggtc 480caagcgctgc tcctgctcgt ccctgatgga taaagagtgt gtctacttct gccacctgga 540catcatttgg gtcaacactc ccgagcacgt tgttccgtat ggacttggaa gccctaggtc 600caagagagcc ttggagaatt tacttcccac aaaggcaaca gaccgtgaaa atagatgcca 660atgtgctagc caaaaagaca agaagtgctg gaatttttgc caagcaggaa aagaactcag 720ggctgaagac attatggaga aagactggaa taatcataag aaaggaaaag actgttccaa 780gcttgggaaa aagtgtattt atcagcagtt agtgagagga agaaaaatca gaagaagttc 840agaggaacac ctaagacaaa ccaggtcgga gaccatgaga aacagcgtca aatcatcttt 900tcatgatccc aagctgaaag gcaagccctc cagagagcgt tatgtgaccc acaaccgagc 960acattggtga cagaccttcg gggcctgtct gaagccatag cctccacgga gagccctgtg 1020gccgactctg cactctccac cctggctggg atcagagcag gagcatcctc tgctggttcc 1080tgactggcaa aggaccagcg tcctcgttca aaacattcca agaaaggtta aggagttccc 1140ccaaccatct tcactggctt ccatcagtgg taactgcttt ggtctcttct ttcatctggg 1200gatgacaatg gacctctcag cagaaacaca cagtcacatt cgaattcggg tggcatcctc 1260cggagagaga gagaggaagg agattccaca caggggtgga gtttctgacg aaggtcctaa 1320gggagtgttt gtgtctgact caggcgcctg gcacatttca gggagaaact ccaaagtcca 1380cacaaagatt ttctaaggaa tgcacaaatt gaaaacacac tcaaaagaca aacatgcaag 1440taaagaaaaa aaaaagaaag acttttgttt aaatttgtaa aatgcaaaac tgaatgaaac 1500tgttactacc ataaatcagg atatgtttca tgaatatgag tctacctcac ctatattgca 1560ctctggcaga agtatttccc acatttaatt attgcctccc caaactcttc ccacccctgc 1620tgccccttcc tccatccccc atactaaatc ctagcctcgt agaagtctgg tctaatgtgt 1680cagcagtaga tataatattt tcatggtaat ctactagctc tgatccataa gaaaaaaaag 1740atcattaaat caggagattc cctgtccttg atttttggag acacaatggt atagggttgt 1800ttatgaaata tattgaaaag taagtgtttg ttacgcttta aagcagtaaa attattttcc 1860tttatataac cggctaatga aagaggttgg attgaatttt gatgtactta tttttttata 1920gatatttata ttcaaacaat ttattcctta tatttaccat gttaaatatc tgtttgggca 1980ggccatattg gtctatgtat ttttaaaata tgtatttcta aatgaaattg agaacatgct 2040ttgttttgcc tgtcaaggta atgactttag aaaataaata tttttttcct tactgtaaaa 2100aaaaaaaaa 2109158272DNAHomo sapiens 15gcccgcgccg gctgtgctgc acagggggag gagagggaac cccaggcgcg agcgggaaga 60ggggacctgc agccacaact tctctggtcc tctgcatccc ttctgtccct ccacccgtcc 120ccttccccac cctctggccc ccaccttctt ggaggcgaca acccccggga ggcattagaa 180gggatttttc ccgcaggttg cgaagggaag caaacttggt ggcaacttgc ctcccggtgc 240gggcgtctct cccccaccgt ctcaacatgc ttaggggtcc ggggcccggg ctgctgctgc 300tggccgtcca gtgcctgggg acagcggtgc cctccacggg agcctcgaag agcaagaggc 360aggctcagca aatggttcag ccccagtccc cggtggctgt cagtcaaagc aagcccggtt 420gttatgacaa tggaaaacac tatcagataa atcaacagtg ggagcggacc tacctaggca 480atgcgttggt ttgtacttgt tatggaggaa gccgaggttt taactgcgag agtaaacctg 540aagctgaaga gacttgcttt gacaagtaca ctgggaacac ttaccgagtg ggtgacactt 600atgagcgtcc taaagactcc atgatctggg actgtacctg catcggggct gggcgaggga 660gaataagctg taccatcgca aaccgctgcc atgaaggggg tcagtcctac aagattggtg 720acacctggag gagaccacat gagactggtg gttacatgtt agagtgtgtg tgtcttggta 780atggaaaagg agaatggacc tgcaagccca tagctgagaa gtgttttgat catgctgctg 840ggacttccta tgtggtcgga gaaacgtggg agaagcccta ccaaggctgg atgatggtag 900attgtacttg cctgggagaa ggcagcggac gcatcacttg cacttctaga aatagatgca 960acgatcagga cacaaggaca tcctatagaa ttggagacac ctggagcaag aaggataatc 1020gaggaaacct gctccagtgc atctgcacag gcaacggccg aggagagtgg aagtgtgaga 1080ggcacacctc tgtgcagacc acatcgagcg gatctggccc cttcaccgat gttcgtgcag 1140ctgtttacca accgcagcct cacccccagc ctcctcccta tggccactgt gtcacagaca 1200gtggtgtggt ctactctgtg gggatgcagt ggctgaagac acaaggaaat aagcaaatgc 1260tttgcacgtg cctgggcaac ggagtcagct gccaagagac agctgtaacc cagacttacg 1320gtggcaactc aaatggagag ccatgtgtct taccattcac ctacaatggc aggacgttct 1380actcctgcac cacagaaggg cgacaggacg gacatctttg gtgcagcaca acttcgaatt 1440atgagcagga ccagaaatac tctttctgca cagaccacac tgttttggtt cagactcgag 1500gaggaaattc caatggtgcc ttgtgccact tccccttcct atacaacaac cacaattaca 1560ctgattgcac ttctgagggc agaagagaca acatgaagtg gtgtgggacc acacagaact 1620atgatgccga ccagaagttt gggttctgcc ccatggctgc ccacgaggaa atctgcacaa 1680ccaatgaagg ggtcatgtac cgcattggag atcagtggga taagcagcat gacatgggtc 1740acatgatgag gtgcacgtgt gttgggaatg gtcgtgggga atggacatgc attgcctact 1800cgcagcttcg agatcagtgc attgttgatg acatcactta caatgtgaac gacacattcc 1860acaagcgtca tgaagagggg cacatgctga actgtacatg cttcggtcag ggtcggggca 1920ggtggaagtg tgatcccgtc gaccaatgcc aggattcaga gactgggacg ttttatcaaa 1980ttggagattc atgggagaag tatgtgcatg gtgtcagata ccagtgctac tgctatggcc 2040gtggcattgg ggagtggcat tgccaacctt tacagaccta tccaagctca agtggtcctg 2100tcgaagtatt tatcactgag actccgagtc agcccaactc ccaccccatc cagtggaatg 2160caccacagcc atctcacatt tccaagtaca ttctcaggtg gagacctaaa aattctgtag 2220gccgttggaa ggaagctacc ataccaggcc acttaaactc ctacaccatc aaaggcctga 2280agcctggtgt ggtatacgag ggccagctca tcagcatcca gcagtacggc caccaagaag 2340tgactcgctt tgacttcacc accaccagca ccagcacacc tgtgaccagc aacaccgtga 2400caggagagac gactcccttt tctcctcttg tggccacttc tgaatctgtg accgaaatca 2460cagccagtag ctttgtggtc tcctgggtct cagcttccga caccgtgtcg ggattccggg 2520tggaatatga gctgagtgag gagggagatg agccacagta cctggatctt ccaagcacag 2580ccacttctgt gaacatccct gacctgcttc ctggccgaaa atacattgta aatgtctatc 2640agatatctga ggatggggag cagagtttga tcctgtctac ttcacaaaca acagcgcctg 2700atgcccctcc tgacccgact gtggaccaag ttgatgacac ctcaattgtt gttcgctgga 2760gcagacccca ggctcccatc acagggtaca gaatagtcta ttcgccatca gtagaaggta 2820gcagcacaga actcaacctt cctgaaactg caaactccgt caccctcagt gacttgcaac 2880ctggtgttca gtataacatc actatctatg ctgtggaaga aaatcaagaa agtacacctg 2940ttgtcattca acaagaaacc actggcaccc cacgctcaga tacagtgccc tctcccaggg 3000acctgcagtt tgtggaagtg acagacgtga aggtcaccat catgtggaca ccgcctgaga 3060gtgcagtgac cggctaccgt gtggatgtga tccccgtcaa cctgcctggc gagcacgggc 3120agaggctgcc catcagcagg aacacctttg cagaagtcac cgggctgtcc cctggggtca 3180cctattactt caaagtcttt gcagtgagcc atgggaggga gagcaagcct ctgactgctc 3240aacagacaac caaactggat gctcccacta acctccagtt tgtcaatgaa actgattcta 3300ctgtcctggt gagatggact ccacctcggg cccagataac aggataccga ctgaccgtgg 3360gccttacccg aagaggacag cccaggcagt acaatgtggg tccctctgtc tccaagtacc 3420cactgaggaa tctgcagcct gcatctgagt acaccgtatc cctcgtggcc ataaagggca 3480accaagagag ccccaaagcc actggagtct ttaccacact gcagcctggg agctctattc 3540caccttacaa caccgaggtg actgagacca ccattgtgat cacatggacg cctgctccaa 3600gaattggttt taagctgggt gtacgaccaa gccagggagg agaggcacca cgagaagtga 3660cttcagactc aggaagcatc gttgtgtccg gcttgactcc aggagtagaa tacgtctaca 3720ccatccaagt cctgagagat ggacaggaaa gagatgcgcc aattgtaaac aaagtggtga 3780caccattgtc tccaccaaca aacttgcatc tggaggcaaa ccctgacact ggagtgctca 3840cagtctcctg ggagaggagc accaccccag acattactgg ttatagaatt accacaaccc 3900ctacaaacgg ccagcaggga aattctttgg aagaagtggt ccatgctgat cagagctcct 3960gcacttttga taacctgagt cccggcctgg agtacaatgt cagtgtttac actgtcaagg 4020atgacaagga aagtgtccct atctctgata ccatcatccc agctgttcct cctcccactg 4080acctgcgatt caccaacatt ggtccagaca ccatgcgtgt cacctgggct ccacccccat 4140ccattgattt aaccaacttc ctggtgcgtt actcacctgt gaaaaatgag gaagatgttg 4200cagagttgtc aatttctcct tcagacaatg cagtggtctt aacaaatctc ctgcctggta 4260cagaatatgt agtgagtgtc tccagtgtct acgaacaaca tgagagcaca cctcttagag 4320gaagacagaa aacaggtctt gattccccaa ctggcattga cttttctgat attactgcca 4380actcttttac tgtgcactgg attgctcctc gagccaccat cactggctac aggatccgcc 4440atcatcccga gcacttcagt gggagacctc gagaagatcg ggtgccccac tctcggaatt 4500ccatcaccct caccaacctc actccaggca cagagtatgt ggtcagcatc gttgctctta 4560atggcagaga ggaaagtccc ttattgattg gccaacaatc aacagtttct gatgttccga 4620gggacctgga agttgttgct gcgaccccca ccagcctact gatcagctgg gatgctcctg 4680ctgtcacagt gagatattac aggatcactt acggagagac aggaggaaat agccctgtcc 4740aggagttcac tgtgcctggg agcaagtcta cagctaccat cagcggcctt aaacctggag 4800ttgattatac catcactgtg tatgctgtca ctggccgtgg agacagcccc gcaagcagca 4860agccaatttc cattaattac cgaacagaaa ttgacaaacc atcccagatg caagtgaccg 4920atgttcagga caacagcatt agtgtcaagt ggctgccttc aagttcccct gttactggtt 4980acagagtaac caccactccc aaaaatggac caggaccaac aaaaactaaa actgcaggtc 5040cagatcaaac agaaatgact attgaaggct tgcagcccac agtggagtat gtggttagtg 5100tctatgctca gaatccaagc ggagagagtc agcctctggt tcagactgca gtaaccacta 5160ttcctgcacc aactgacctg aagttcactc aggtcacacc cacaagcctg agcgcccagt 5220ggacaccacc caatgttcag ctcactggat atcgagtgcg ggtgaccccc aaggagaaga 5280ccggaccaat gaaagaaatc aaccttgctc ctgacagctc atccgtggtt gtatcaggac 5340ttatggtggc caccaaatat gaagtgagtg tctatgctct taaggacact ttgacaagca 5400gaccagctca gggagttgtc accactctgg agaatgtcag cccaccaaga agggctcgtg 5460tgacagatgc tactgagacc accatcacca ttagctggag aaccaagact gagacgatca 5520ctggcttcca agttgatgcc gttccagcca atggccagac tccaatccag agaaccatca 5580agccagatgt cagaagctac accatcacag gtttacaacc aggcactgac tacaagatct 5640acctgtacac cttgaatgac aatgctcgga gctcccctgt ggtcatcgac gcctccactg 5700ccattgatgc accatccaac ctgcgtttcc tggccaccac acccaattcc ttgctggtat 5760catggcagcc gccacgtgcc aggattaccg gctacatcat caagtatgag aagcctgggt 5820ctcctcccag agaagtggtc cctcggcccc gccctggtgt cacagaggct actattactg 5880gcctggaacc gggaaccgaa tatacaattt atgtcattgc cctgaagaat aatcagaaga 5940gcgagcccct gattggaagg aaaaagacag acgagcttcc ccaactggta acccttccac 6000accccaatct tcatggacca gagatcttgg atgttccttc cacagttcaa aagacccctt 6060tcgtcaccca ccctgggtat gacactggaa atggtattca gcttcctggc acttctggtc 6120agcaacccag tgttgggcaa caaatgatct ttgaggaaca tggttttagg cggaccacac 6180cgcccacaac ggccaccccc ataaggcata ggccaagacc atacccgccg aatgtaggtg 6240aggaaatcca aattggtcac atccccaggg aagatgtaga ctatcacctg tacccacacg 6300gtccgggact caatccaaat gcctctacag gacaagaagc tctctctcag acaaccatct 6360catgggcccc attccaggac acttctgagt acatcatttc atgtcatcct gttggcactg 6420atgaagaacc cttacagttc agggttcctg gaacttctac cagtgccact ctgacaggcc 6480tcaccagagg tgccacctac aacatcatag tggaggcact gaaagaccag cagaggcata 6540aggttcggga agaggttgtt accgtgggca actctgtcaa cgaaggcttg aaccaaccta 6600cggatgactc gtgctttgac ccctacacag tttcccatta tgccgttgga gatgagtggg 6660aacgaatgtc tgaatcaggc tttaaactgt tgtgccagtg cttaggcttt ggaagtggtc 6720atttcagatg tgattcatct agatggtgcc atgacaatgg tgtgaactac aagattggag 6780agaagtggga ccgtcaggga gaaaatggcc agatgatgag ctgcacatgt cttgggaacg 6840gaaaaggaga attcaagtgt gaccctcatg aggcaacgtg ttatgatgat gggaagacat 6900accacgtagg agaacagtgg cagaaggaat atctcggtgc catttgctcc tgcacatgct 6960ttggaggcca gcggggctgg cgctgtgaca actgccgcag acctgggggt gaacccagtc 7020ccgaaggcac tactggccag tcctacaacc agtattctca gagataccat cagagaacaa 7080acactaatgt taattgccca attgagtgct tcatgccttt agatgtacag gctgacagag 7140aagattcccg agagtaaatc atctttccaa tccagaggaa caagcatgtc tctctgccaa 7200gatccatcta aactggagtg atgttagcag acccagctta gagttcttct ttctttctta 7260agccctttgc tctggaggaa gttctccagc ttcagctcaa ctcacagctt ctccaagcat 7320caccctggga gtttcctgag ggttttctca taaatgaggg ctgcacattg cctgttctgc 7380ttcgaagtat tcaataccgc tcagtatttt aaatgaagtg attctaagat ttggtttggg 7440atcaatagga aagcatatgc agccaaccaa gatgcaaatg ttttgaaatg atatgaccaa 7500aattttaagt aggaaagtca cccaaacact tctgctttca cttaagtgtc tggcccgcaa 7560tactgtagga acaagcatga tcttgttact gtgatatttt aaatatccac agtactcact 7620ttttccaaat gatcctagta attgcctaga aatatctttc tcttacctgt tatttatcaa 7680tttttcccag tatttttata cggaaaaaat tgtattgaaa acacttagta tgcagttgat 7740aagaggaatt tggtataatt atggtgggtg attatttttt atactgtatg tgccaaagct 7800ttactactgt ggaaagacaa ctgttttaat aaaagattta cattccacaa cttgaagttc 7860atctatttga tataagacac cttcggggga aataattcct gtgaatattc tttttcaatt 7920cagcaaacat ttgaaaatct atgatgtgca agtctaattg ttgatttcag tacaagattt 7980tctaaatcag ttgctacaaa aactgattgg tttttgtcac ttcatctctt cactaatgga 8040gatagcttta cactttctgc tttaatagat ttaagtggac cccaatattt attaaaattg 8100ctagtttacc gttcagaagt ataatagaaa taatctttag ttgctctttt ctaaccattg 8160taattcttcc cttcttccct ccacctttcc ttcattgaat aaacctctgt tcaaagagat 8220tgcctgcaag ggaaataaaa atgactaaga tattaaaaaa aaaaaaaaaa aa 8272162397DNAHomo sapiens 16gcacacactc atcgaaaaaa atttggatta ttagaagaga gaggtctgcg gcttccacac 60cgtacagcgt ggtttttctt ctcggtataa aagcaaagtt gtttttgata cgtgacagtt 120tcccacaagc caggctgatc cttttctgtc agtccacttc accaagcctg cccttggaca 180aggacccgat gcccaacccc aggcctggca agccctcggc cccttccttg gcccttggcc 240catccccagg agcctcgccc agctggaggg ctgcacccaa agcctcagac ctgctggggg 300cccggggccc agggggaacc ttccagggcc gagatcttcg aggcggggcc catgcctcct 360cttcttcctt gaaccccatg ccaccatcgc agctgcagct gcccacactg cccctagtca 420tggtggcacc ctccggggca cggctgggcc ccttgcccca cttacaggca ctcctccagg 480acaggccaca tttcatgcac cagctctcaa cggtggatgc ccacgcccgg acccctgtgc 540tgcaggtgca ccccctggag agcccagcca tgatcagcct cacaccaccc accaccgcca 600ctggggtctt ctccctcaag gcccggcctg gcctcccacc tgggatcaac gtggccagcc 660tggaatgggt gtccagggag ccggcactgc tctgcacctt

cccaaatccc agtgcaccca 720ggaaggacag caccctttcg gctgtgcccc agagctccta cccactgctg gcaaatggtg 780tctgcaagtg gcccggatgt gagaaggtct tcgaagagcc agaggacttc ctcaagcact 840gccaggcgga ccatcttctg gatgagaagg gcagggcaca atgtctcctc cagagagaga 900tggtacagtc tctggagcag cagctggtgc tggagaagga gaagctgagt gccatgcagg 960cccacctggc tgggaaaatg gcactgacca aggcttcatc tgtggcatca tccgacaagg 1020gctcctgctg catcgtagct gctggcagcc aaggccctgt cgtcccagcc tggtctggcc 1080cccgggaggc ccctgacagc ctgtttgctg tccggaggca cctgtggggt agccatggaa 1140acagcacatt cccagagttc ctccacaaca tggactactt caagttccac aacatgcgac 1200cccctttcac ctacgccacg ctcatccgct gggccatcct ggaggctcca gagaagcagc 1260ggacactcaa tgagatctac cactggttca cacgcatgtt tgccttcttc agaaaccatc 1320ctgccacctg gaagaacgcc atccgccaca acctgagtct gcacaagtgc tttgtgcggg 1380tggagagcga gaagggggct gtgtggaccg tggatgagct ggagttccgc aagaaacgga 1440gccagaggcc cagcaggtgt tccaacccta cacctggccc ctgacctcaa gatcaaggaa 1500aggaggatgg acgaacaggg gccaaactgg tgggaggcag aggtggtggg ggcagggatg 1560ataggccctg gatgtgccca cagggaccaa gaagtgaggt ttccactgtc ttgcctgcca 1620gggcccctgt tcccccgctg gcagccaccc cctcccccat catatccttt gccccaaggc 1680tgctcagagg ggccccggtc ctggccccag cccccacctc cgccccagac acacccccca 1740gtcgagccct gcagccaaac agagccttca caaccagcca cacagagcct gcctcagctg 1800ctcgcacaga ttacttcagg gctggaaaag tcacacagac acacaaaatg tcacaatcct 1860gtccctcact caacacaaac cccaaaacac agagagcctg cctcagtaca ctcaaacaac 1920ctcaaagctg catcatcaca caatcacaca caagcacagc cctgacaacc cacacacccc 1980aaggcacgca cccacagcca gcctcagggc ccacaggggc actgtcaaca caggggtgtg 2040cccagaggcc tacacagaag cagcgtcagt accctcagga tctgaggtcc caacacgtgc 2100tcgctcacac acacggcctg ttagaattca cctgtgtatc tcacgcatat gcacacgcac 2160agccccccag tgggtctctt gagtcccgtg cagacacaca cagccacaca cactgccttg 2220ccaaaaatac cccgtgtctc ccctgccact cacctcactc ccattccctg agccctgatc 2280catgcctcag cttagactgc agaggaacta ctcatttatt tgggatccaa ggcccccaac 2340ccacagtacc gtccccaata aactgcagcc gagctcccca caaaaaaaaa aaaaaaa 2397171936DNAHomo sapiens 17acagctcttg ccaggcaagg cagccgacca caggtgagtc ttggcatcta ccgttttcaa 60gtgaccagga tgaagacact ccagtttttc ttccttttct gttgctggaa agcaatctgc 120tgcaatagct gtgagctgac caacatcacc attgcaatag agaaagaaga atgtcgtttc 180tgcataagca tcaacaccac ttggtgtgct ggctactgct acaccaggga tctggtgtat 240aaggacccag ccaggcccaa aatccagaaa acatgtacct tcaaggaact ggtatacgaa 300acagtgagag tgcccggctg tgctcaccat gcagattcct tgtatacata cccagtggcc 360acccagtgtc actgtggcaa gtgtgacagc gacagcactg attgtactgt gcgaggcctg 420gggcccagct actgctcctt tggtgaaatg aaagaataaa gatcagtgga catttcaggc 480cacataccct tgtcctgaag gaccaagata ttcaaaaagt ctgtgtgtgt gcaatgtgcc 540caggggacaa accactggat caggggattc agactctact gatccctggt ctactggcag 600agggaactct gggaattgag agtgctgggg gccaggactc catcatgatt cagctctata 660ttcctaggtc tgatttcata aggtttattc agtcttaact cacagacttg tgcctggttt 720cttctttaaa aatcttagaa atcttctcag gcaatgcctc tctcttaggg ggaaacataa 780gcctagaagg aggaagcagt aatgggagtg agtgaaagaa ctaactgcag cagtcttctg 840gtagactctt gggccctcta gagcaaggtc agcatcttca gcattgtagc gtcaatgcct 900agcactctgc ctggaactta gaaacacaac aatgacttct ttagatcaga aaggtcaagg 960gtagaaaata ctggaagacg atgtttgagg taagctgatg aggctgcccg cagccacacc 1020agtcccatga aagttagtgg catcagttcc acctcgcctt ttctccagca catggagtat 1080tgagacatga tgtatctttc tgaattgttt ggtacagatg gggagtaaca gagctcaaga 1140tttccaagct attactacca agcctgttag ttaagggcaa aggcaagaaa ttgtaatttg 1200gggctgtgga aattagcctg cctctattca ttacttaaac aaattgatca catgctacta 1260ggctcctgca aaactccttt ttgagataaa gggaaaaaac caaactatct caccctaccc 1320tccctaggat ccacttcttt ggaatgacaa aggatttgaa agtaggtttg aaagcagttt 1380cagcaattta ataaatataa ttaatttgtc tacaaatata tttgtataaa taaatagctc 1440ctttagaaag aattagccat gggggacgag gggaaactgc tgttttctag gatcctgtct 1500acatcaatct tctattttat ccatccatgt tctcccaaat ctgtgctttc tttcaacagg 1560ttatatatta aaactatttc atgagttgat ttcttttaaa cgtgttaact gtcttagtta 1620tgcactcagt ttcacactca tattgtttaa ctaatttatt taaatcttat ttttttaata 1680aagatgctag ccaccagagt cacaggcttg gattgtttta tgtacaaaca gatgacttag 1740atattctgta ttttataata ttagtggaat gaaatcttaa aatataattc ccagtgtttc 1800tataaatatt acctttcctt atctttggag atattaaaaa taattttgtt ggatttctga 1860agtgttttgt cacttaaatt tcctgtcatt ttttgaagac attttctgat gtaatttggg 1920agaaaaaaag cataga 1936181834DNAHomo sapiens 18ttgggaaggg tttccagaag gtgggaaatg tcacctgatt cacactgaac ttttgaaagc 60tccccacccc caaggagccg cgcacaccct cgctcgcggc cgccctccca cagccccaca 120cactgggaga ccgcccaccg caaaccgcgg agacccccgt ctagatttaa agcgcggctg 180cgcccggctt ctgacgtcca ttgaatcgcg cgggcggccg gcggcgagcg cggggctgcg 240ccgggatcgc tgcgccctcc gccgctggcc tctgcgacgc gcgccgctcg cccgagccac 300ccgccgccgc gccggctccc cgcgccgctg cgctcctcgc cccgcgcctg cccccaggat 360ggtccgcgcg aggcaccagc cgggtgggct ttgcctcctg ctgctgctgc tctgccagtt 420catggaggac cgcagtgccc aggctgggaa ctgctggctc cgtcaagcga agaacggccg 480ctgccaggtc ctgtacaaga ccgaactgag caaggaggag tgctgcagca ccggccggct 540gagcacctcg tggaccgagg aggacgtgaa tgacaacaca ctcttcaagt ggatgatttt 600caacgggggc gcccccaact gcatcccctg taaagaaacg tgtgagaacg tggactgtgg 660acctgggaaa aaatgccgaa tgaacaagaa gaacaaaccc cgctgcgtct gcgccccgga 720ttgttccaac atcacctgga agggtccagt ctgcgggctg gatgggaaaa cctaccgcaa 780tgaatgtgca ctcctaaagg caagatgtaa agagcagcca gaactggaag tccagtacca 840aggcagatgt aaaaagactt gtcgggatgt tttctgtcca ggcagctcca catgtgtggt 900ggaccagacc aataatgcct actgtgtgac ctgtaatcgg atttgcccag agcctgcttc 960ctctgagcaa tatctctgtg ggaatgatgg agtcacctac tccagtgcct gccacctgag 1020aaaggctacc tgcctgctgg gcagatctat tggattagcc tatgagggaa agtgtatcaa 1080agcaaagtcc tgtgaagata tccagtgcac tggtgggaaa aaatgtttat gggatttcaa 1140ggttgggaga ggccggtgtt ccctctgtga tgagctgtgc cctgacagta agtcggatga 1200gcctgtctgt gccagtgaca atgccactta tgccagcgag tgtgccatga aggaagctgc 1260ctgctcctca ggtgtgctac tggaagtaaa gcactccgga tcttgcaact ccatttcgga 1320agacaccgag gaagaggagg aagatgaaga ccaggactac agctttccta tatcttctat 1380tctagagtgg taaactctct ataagtgttc agtgttgaca tagcctttgt gcaaaaaaaa 1440aaaaaaaaaa aaagaaaaag aaaaaaagaa aaatatattg tccatactgt aaataagtgt 1500atgcttattt atttgggggg aaaactatac attaaaggac ctttgtccta aagctctctc 1560ccaggccacc ttgttactca ttggacacgg agaggcattc attgtgaggt ctactggatg 1620aggcccatag ttgagacttg tagacattta tttatactgt gtcatgtttt ataatttata 1680cataaaatgt ctggttgact gtataccttg tttttgaaga aatttattcg tgaaaggaag 1740agcagttgtt atttattgtg aggtctcttg cttgtaaagt aaaagctttt tttccttgta 1800aaccatttaa gtccattcct tactattcac tcac 1834192525DNAHomo sapiens 19gggaagtcgg tgccgctgcc gtctctgcgt tcgccatgcg tcccggggcg ccagggccac 60tctggcctct gccctggggg gccctggctt gggccgtggg cttcgtgagc tccatgggct 120cggggaaccc cgcgcccggt ggtgtttgct ggctccagca gggccaggag gccacctgca 180gcctggtgct ccagactgat gtcacccggg ccgagtgctg tgcctccggc aacattgaca 240ccgcctggtc caacctcacc cacccgggga acaagatcaa cctcctcggc ttcttgggcc 300ttgtccactg ccttccctgc aaagattcgt gcgacggcgt ggagtgcggc ccgggcaagg 360cgtgccgcat gctggggggc cgcccgcgct gcgagtgcgc gcccgactgc tcggggctcc 420cggcgcggct gcaggtctgc ggctcagacg gcgccaccta ccgcgacgag tgcgagctgc 480gcgccgcgcg ctgccgcggc cacccggacc tgagcgtcat gtaccggggc cgctgccgca 540agtcctgtga gcacgtggtg tgcccgcggc cacagtcgtg cgtcgtggac cagacgggca 600gcgcccactg cgtggtgtgt cgagcggcgc cctgccctgt gccctccagc cccggccagg 660agctttgcgg caacaacaac gtcacctaca tctcctcgtg ccacatgcgc caggccacct 720gcttcctggg ccgctccatc ggcgtgcgcc acgcgggcag ctgcgcaggc acccctgagg 780agccgccagg tggtgagtct gcagaagagg aagagaactt cgtgtgagcc tgcaggacag 840gcctgggcct ggtgcccgag gccccccatc atcccctgtt atttattgcc acagcagagt 900ctaatttata tgccacggac actccttaga gcccggattc ggaccacttg gggatcccag 960aacctccctg acgatatcct ggaaggactg aggaagggag gcctgggggc cggctggtgg 1020gtgggataga cctgcgttcc ggacactgag cgcctgattt agggcccttc tctaggatgc 1080cccagcccct accctaagac ctattgccgg ggaggattcc acacttccgc tcctttgggg 1140ataaacctat taattattgc tactatcaag agggctgggc attctctgct ggtaattcct 1200gaagaggcat gactgctttt ctcagcccca agcctctagt ctgggtgtgt acggagggtc 1260tagcctgggt gtgtacggag ggtctagcct gggtgagtac ggagggtcta gcctgggtga 1320gtacggaggg tctagcctgg gtgagtacgg agggtctagc ctgggtgtgt atggaggatc 1380tagcctgggt gagtatggag ggtctagcct gggtgagtat ggagggtcta gcctgggtgt 1440gtatggaggg tctagcctgg gtgagtatgg agggtctagc ctgggtgtgt atggagggtc 1500tagcctgggt gagtatggag ggtctagcct gggtgtgtac ggagggtcta gtctgagtgc 1560gtgtggggac ctcagaacac tgtgacctta gcccagcaag ccaggccctt catgaaggcc 1620aagaaggctg ccaccattcc ctgccagccc aagaactcca gcttccccac tgcctctgtg 1680tgcccctttg cgtcctgtga aggccattga gaaatgccca gtgtgccccc tgggaaaggg 1740cacggcctgt gctcctgaca cgggctgtgc ttggccacag aaccacccag cgtctcccct 1800gctgctgtcc acgtcagttc atgaggcaac gtcgcgtggt ctcagacgtg gagcagccag 1860cggcagctca gagcagggca ctgtgtccgg cggagccaag tccactctgg gggagctctg 1920gcggggacca cgggccactg ctcacccact ggccccgagg ggggtgtaga cgccaagact 1980cacgcatgtg tgacatccgg agtcctggag ccgggtgtcc cagtggcacc actaggtgcc 2040tgctgcctcc acagtggggt tcacacccag ggctccttgg tcccccacaa cctgccccgg 2100ccaggcctgc agacccagac tccagccaga cctgcctcac ccaccaatgc agccggggct 2160ggcgacacca gccaggtgct ggtcttgggc cagttctccc acgacggctc accctcccct 2220ccatctgcgt tgatgctcag aatcgcctac ctgtgcctgc gtgtaaacca cagcctcaga 2280ccagctatgg ggagaggaca acacggagga tatccagctt ccccggtctg gggtgaggaa 2340tgtggggagc ttgggcatcc tcctccagcc tcctccagcc cccaggcagt gccttacctg 2400tggtgcccag aaaagtgccc ctaggttggt gggtctacag gagcctcagc caggcagccc 2460accccaccct ggggccctgc ctcaccaagg aaataaagac tcaagccatt taaaaaaaaa 2520aaaaa 2525201398DNAHomo sapiens 20ggagagcggg gccctttgtc ctccagtggc tggtaggcag tggctgggag gcagcggccc 60aattagtgtc gtgcggcccg tggcgaggcg aggtccgggg agcgagcgag caagcaaggc 120gggaggggtg gccggagctg cggcggctgg cacaggagga ggagcccggg cgggcgaggg 180gcggccggag agcgccaggg cctgagctgc cggagcggcg cctgtgagtg agtgcagaaa 240gcaggcgccc gcgcgctagc cgtggcagga gcagcccgca cgccgcgctc tctccctggg 300cgacctgcag tttgcaatat gactttggag gaattctcgg ctggagagca gaagaccgaa 360aggatggata aggtggggga tgccctggag gaagtgctca gcaaagccct gagtcagcgc 420acgatcactg tcggggtgta cgaagcggcc aagctgctca acgtcgaccc cgataacgtg 480gtgttgtgcc tgctggcggc ggacgaggac gacgacagag atgtggctct gcagatccac 540ttcaccctga tccaggcgtt ttgctgcgag aacgacatca acatcctgcg cgtcagcaac 600ccgggccggc tggcggagct cctgctcttg gagaccgacg ctggccccgc ggcgagcgag 660ggcgccgagc agcccccgga cctgcactgc gtgctggtga cgaatccaca ttcatctcaa 720tggaaggatc ctgccttaag tcaacttatt tgtttttgcc gggaaagtcg ctacatggat 780caatgggttc cagtgattaa tctccctgaa cggtgatggc atctgaatga aaataactga 840accaaattgc actgaagttt ttgaaatacc tttgtagtta ctcaagcagt tactccctac 900actgatgcaa ggattacaga aactgatgcc aaggggctga gtgagttcaa ctacatgttc 960tgggggcccg gagatagatg actttgcaga tggaaagagg tgaaaatgaa gaaggaagct 1020gtgttgaaac agaaaaataa gtcaaaagga acaaaaatta caaagaacca tgcaggaagg 1080aaaactatgt attaatttag aatggttgag ttacattaaa ataaaccaaa tatgttaaag 1140tttaagtgtg cagccatagt ttgggtattt ttggtttata tgccctcaag taaaagaaaa 1200gccgaaaggg ttaatcatat ttgaaaacca tattttattg tattttgatg agatattaaa 1260ttctcaaagt tttattataa attctactaa gttattttat gacatgaaaa gttatttatg 1320ctataaattt tttgaaacac aatacctaca ataaactggt atgaataatt gcatcatttc 1380aaaaaaaaaa aaaaaaaa 1398211393DNAHomo sapiens 21tcagatcgcc gaagcgtcgg actaccgttg gtttccgcaa cttcctggat tatcctcgcc 60aaggactttg caatatattt ttccgccttt tctggaagga tttcgctgct tcccgaaggt 120cttggacgag cgctctagct ctgtgggaag gttttgggct ctctggctcg gattttgcaa 180tttctccctg gggactgccg tggagccgca tccactgtgg attataattg caacatgacg 240ctggaagagc tcgtggcgtg cgacaacgcg gcgcagaaga tgcagacggt gaccgccgcg 300gtggaggagc ttttggtggc cgctcagcgc caggatcgcc tcacagtggg ggtgtacgag 360tcggccaagt tgatgaatgt ggacccagac agcgtggtcc tctgcctctt ggccattgac 420gaggaggagg aggatgacat cgccctgcaa atccacttca cgctcatcca gtccttctgc 480tgtgacaacg acatcaacat cgtgcgggtg tcgggcatgc agcgcctggc gcagctcctg 540ggagagccgg ccgagaccca gggcaccacc gaggcccgag acctgcattg tctcctggtc 600acgaaccctc acacggacgc ctggaagagc cacggcttgg tggaggtggc cagctactgc 660gaagaaagcc ggggcaacaa ccagtgggtc ccctacatct ctcttcagga acgctgaggc 720ccttcccagc agcagaatct gttgagttgc tgccacaaac aaaaaataca ataaatattt 780gaaccccctc ccccccagca caaccccccc aaaacaaccc aacccacgag gaccatcggg 840ggcagagtcg ttggagactg aagaggaaga ggaggaggag aaggggagtg agcggccgcc 900cccagggcgg agatccagga gctggcggcc gccgatccga tggagaaggg gggacccagg 960ccagcaggag acaggacccc cgaagctgag gccttgggat ggagcagaag ccggagtggc 1020ggggcacgct gccgccttcc ccatcacgga gggtccagac tgtccactcg ggggtggagt 1080gagactgact gcaagcccca ccctccttga gactggagct ggcgtctgca tacgagagac 1140ttggttgaac ttggttggtc cttgtctgca ccctcgacaa gaccacactt tgggacttgg 1200gagctggggc tgaagttgct ctgtacccat gaactcccag tttgcgaatt atagagacaa 1260tctattttgt tacttgcact tgttattcga accactgaga gcgagatggg aagcatagat 1320atctatattt ttatttctac tatgagggcc ttgtaataaa tttctaaagc ctctgaaaaa 1380aaaaaaaaaa aaa 1393225843DNAHomo sapiens 22ttggttgctg gtccacttac aaacactttt catatttgta tgtctttcca atggttatcc 60tgttttgttc atttcaggca tatggccctg atcagattaa ctgacatgat gtatatgcaa 120agccttttga gttcttcaga aaaataaatt atcttattca agactgattg cttataagga 180acttattata gctaatatag taggcacaat tttttttttg taattctcct agatgagtca 240gaacttagtt ttgacgtagg taaaaatttt atggtcacaa atctcaggtg tgagaaaatc 300tctttccttg atactctata taaatagagg atataaatat ttcaagtctg gaagtagtga 360gagaagctgg taattctgga catatagtga cagtcaaaaa ggagctcagg tacaggactg 420gtctaagctg ctcaagattc aggagacagc cagtacacag agaagctgag gagatacata 480agatatatct aaaacattta tctaaccttc tgtggtaaca agctccttaa aggggctgga 540tgatgttgtg ttcacttttt atcaccagca aaggctaaga taatgtatat agtaaatatt 600tagtaactat ttattaaata aataaatatt taagacagaa taaacaagta taataaatga 660accaataaga atgcaccatc taagtcaaaa tagccacttt tatccttaac attgtacctg 720ctttggctgc tgcagaagca aacttgttgg cattagacaa atcaagctgg tgatttaata 780aattccaatg taagtcttac cagtattgat gaataactat ccagcactca ccatgaaagt 840taaagaaaca acacagaaaa agttcctaag tggtcccaat ttgaaatgat cagataacct 900ataaaagaac atattcatat tatactaaca taaacacata taaatgcact tacagcagtt 960acacagtatt ctcttcaata actagtttcc ttatgcatta atgtgtaata acagcaacta 1020caatatttag ataattataa aaaccaaggc aataatttaa aaactgatta accgttttac 1080tctaacttaa gcatggattg gatcagtaag attgattaat aaatttgaat gcagtcagtt 1140ggattgattc taatttaaag ttttaatttg ttgtagaata attttaagtg aatatatttg 1200tccagtgttc gagtgctcaa cagtgtgttt gaaaaggaaa acaaagaaat gtttttgaga 1260aatgtgttaa ttccttaaga caatggattt taattggatc tagttgtttt catttttctt 1320cattatcatt atacatctgt atgttggaca gaacactaac actaaatagt ttttagaaaa 1380attttttaaa gttatttaaa tcataatatc atgactgact tttaaattca aaattaggct 1440gtgactatcc ttcttcactt aggaagagtg ttgtgaaagc cagaccatct gctgaggtgc 1500tacagttaca tgtggccctc agaatgcatt tggcctgctc tgttttagca ctctgttgga 1560ttaccaatac acaaaacaag ttaaccttga tctttcacat taagtatctc agggacaaaa 1620tttgacatac gtctaaacct gtgacgtttc catctaaaga aggcagaaat aaaacaggac 1680tttagattcg gttacaataa aatatcagat gcaccagaga cacaaggctt gaagctctgt 1740cctgggaaaa tatggcaaac agtgcctctc ctgaacagaa tcaaaatcac tgttcagcca 1800tcaacaacag catcccactg atgcagggca acctccccac tctgaccttg tctggaaaga 1860tccgagtgac ggttactttc ttcctttttc tgctctctgc gacctttaat gcttctttct 1920tgttgaaact tcagaagtgg acacagaaga aagagaaagg gaaaaagctc tcaagaatga 1980agctgctctt aaaacatctg accttagcca acctgttgga gactctgatt gtcatgccac 2040tggatgggat gtggaacatt acagtccaat ggtatgctgg agagttactc tgcaaagttc 2100tcagttatct aaagcttttc tccatgtatg ccccagcctt catgatggtg gtgatcagcc 2160tggaccgctc cctggctatc acgaggcccc tagctttgaa aagcaacagc aaagtcggac 2220agtccatggt tggcctggcc tggatcctca gtagtgtctt tgcaggacca cagttataca 2280tcttcaggat gattcatcta gcagacagct ctggacagac aaaagttttc tctcaatgtg 2340taacacactg cagtttttca caatggtggc atcaagcatt ttataacttt ttcaccttca 2400gctgcctctt catcatccct cttttcatca tgctgatctg caatgcaaaa atcatcttca 2460ccctgacacg ggtccttcat caggaccccc acgaactaca actgaatcag tccaagaaca 2520atataccaag agcacggctg aagactctaa aaatgacggt tgcatttgcc acttcattta 2580ctgtctgctg gactccctac tatgtcctag gaatttggta ttggtttgat cctgaaatgt 2640taaacaggtt gtcagaccca gtaaatcact tcttctttct ctttgccttt ttaaacccat 2700gctttgatcc acttatctat ggatattttt ctctgtgatt gatagactac acaagaagtc 2760atatgaagaa gggtaaggta atgaatctct ccatctggga atgattaaca caaatgttgg 2820agcatgttta catacaaaca aagtaggatt tacacttaag ttatcattct tttagaaact 2880cagtcttcag agcctcaatt attaaggaaa agtcttcagg aaaaatacta aaatattttc 2940tcttcctcat aagcttctaa attaatctct gccttttctg acctcatata acacattatg 3000taggtttctt atcactttct ctttgcataa taatgtacta atatttaaaa taccttcagc 3060ctaaggcaca aggatgccaa aaaaacaaag gtgagaaacc acaacacagg tctaaactca 3120gcatgctttg gtgagttttt ctccaaaagg ggcatattag caattagagt tgtatgctat 3180ataatacata gagcacagag ccctttgccc ataatatcaa ctttccctcc tatagttaaa 3240aagaaaaaaa atgaatctat ttttctcttt ggcttcaaaa gcattctgac atttggagga 3300gtcagtaacc aatcccacca accactccag caacctgaca agactatgag tagttctcct 3360tcatcctatt tatgtggtac aggttgtgaa gtatctctat ataaagggaa attttagagg 3420ggttaggatt tggacagggg tttagaacat tcctctaagc tatctagtct gtggagtttg 3480tggcaattaa ttgccataaa ataacaatgt ttccaaatgc aactaagaaa atactcatag 3540tgagtacgct ctatgcatag tatgacttct attttaatgt gaagaatttt ttgtctctct 3600cctgatctta ctaaatccat atttcataaa taactgagaa taattaaaac aaaattaagc 3660aaatgcacaa gcaaaaagat gcttgataca caaaaggaac tctggagaga aaactacagc 3720ttcagtctgt acagatcaaa gaagacagaa catgtcaggg gaaggaggga aagatcttga 3780tgcagggttt cttaacctgc agtctatgca caacactata tttccatgta atgtttttat 3840ttcagcccta tttgtattat tttgtgcatt taaaaaacac aatcttaagg ggatagacta 3900gactgccaca gcagcccatg gcacaactaa cacctactga

tattcacatt aaatagtatg 3960gtttccaaaa tatgtctgca caacaagacc tctttatgta attcaggctt gtgtctacct 4020cttccatgaa aaatggaaag ggatgaaaat aatgggagta taatacccat ttaatgtgaa 4080aaacataaga gtcttaaaag aaattaagcc atttaacatt ttttaaatag gtaagatacc 4140attatattta tatgagctat gtactgccac aaaaaaagat gaaatgtaat ttctaaatac 4200tccaggtgtg tggtattatg gaaagcaaat tgccaactaa tggcacgtcc tttctttctt 4260tgattttctc ctctcatact tcagttttat agtgttgtgt tgttgttttt ttcatatcct 4320accttacttt ccaattctgt ctcaattgaa ctccctctgt ctactcactc tttcattcat 4380agcttctttt ccattaaact cataccttta attaaccaat tcatggccca gttctacagt 4440tgaattggac aaggctaaaa ttctgtagtg tgctaaaatg ctcaagttgg cacataaacc 4500cattccaaga ttttatagtt cttgtagata acacagggat gtagataagt tgaaacaaaa 4560ccagtgtcct ctaagtctct atcatatact tattcctaaa ctgataattc ttacttctgg 4620atttaaaatc aaaaataaca cacttgtaca gatacaatct aagggcttta tcacacacgt 4680gttaacgaat gtatctcagc ttggttcttc ttgtgtgctc attatggatc tctctgtctt 4740aggaattgcc tcaggcattt ttttttttta cacattaact aaagggctat tcgaaatctt 4800gactcagggg ttcttaacct acatttcatg caaaaaatat atatatttca atgtattttt 4860tattttagtc ctatttgtat tattttatgc atttaaaaac acagtcctga gagggatgga 4920ccagactgcc acagcagctc atagcacaaa aaaaggttaa gaagtcctag ttgactttgt 4980atatatataa agaaatctat tacaataaaa atataacata atctattcat ctatttatat 5040gcaaacataa aaatgtaaat attgaaacaa gattgcttca atatgcttat tgttttcaaa 5100ccaacaaact ctcttaaggt tcaatatgta ataaaaaaca taacacaaat aattattcta 5160tatgaatatt atggttcata aattataatg tataatctat acattataat gtaatatata 5220aactaaaatt tatggcacaa aagataaata tggctttgaa attaaagata ttccactcaa 5280cagacaatat ttcatatttg atattacaat catttatttt atgtcctatt ataataaaag 5340gtgaggactc cttgtaaaaa aggaaatgtt ccacagagtc aatctaatat atcagatatt 5400ggagattcta tcttggtttc tcttccttta cttagcctat aaaactagtt aaaaatggaa 5460tttcttttag caattcagtt tagtacagga gtgacattaa ctaatgacaa taaattaaac 5520aaagcctaca ttagttcaat ttaagcctat tcaacagaaa tatagaaata tagtagctaa 5580aaaaatactc tggggaaggt accacaaaca ttatctacca gggaacatag cataaattag 5640tctgaaattt cctgagagtg actttgtctt agaacttagg tggtagtcat gaagagataa 5700tgtttttagg cagttaaaat acttctagaa ctccatctat tttacctgtg gtccactttc 5760ctacattgaa ccaatgcctt gggcttctct aattactata cattgtgctc atatgaataa 5820aagaaatttt aaaagaaaaa aaa 5843231217DNAHomo sapiens 23agggggcggg gaggggcgca gggctgcgcg ctcgccggcg ctctctttcg gtttggtcgg 60cggctggagg agagtggacc cccccacttt aaggctctgt cctcggcgcg ttcccgccgc 120cccccggtcc cgacgcgggg ctcggggatg cccgccagca tgttcagcat cgacaacatc 180ctagccgccc ggccgcgctg caaggactcg gtgttgccgg tggcgcacag cgcggcggct 240cccgtcgtct tcccggccct gcacggggac tcgctctacg gcgccagcgg cggcgcctcc 300tcggactatg gcgccttcta cccgcgcccc gtggcccccg gcggcgcggg cctcccggcc 360gcggtcagcg gctcccgcct cggctacaac aactacttct acgggcagct gcacgtgcag 420gcggcgcccg tgggcccggc ctgctgcggg gccgtgccgc cgctgggcgc ccagcagtgc 480tcctgcgtcc cgacgccccc aggctacgag ggccccggtt cggtgctggt gtccccggta 540ccgcaccaga tgctgcccta catgaacgtg ggcacgctgt cgcgcaccga gctgcagctt 600ctcaaccagc tgcactgtcg gcggaagcgg cggcaccgca ccatcttcac tgacgagcag 660ctcgaagctc tcgagaacct cttccaggag accaagtacc cggacgtggg cacgcgcgag 720cagctggccc ggaaagtgca cctccgcgag gagaaagtgg aggtctggtt taagaaccgc 780cgcgccaaat ggaggcggca gaagcggtcc tcatcagagg agtcggagaa cgcggagaag 840tggaacaaga cgtcgtcgtc gaaggcgtca ccggagaaga gggaagagga aggtaaaagc 900gatttggact cggacagctg acggccgcgg gacacttgcc cgtattactt acctaactcg 960aaggacttgc acagacagac gatgctactt tcttgcacac gcgctgcctt gcgggagggg 1020gtcgagaaag aggaacgagg agctgtaaat agtgtacaga gccgggaggg tcggcgtctg 1080gggtcagggc gcgcacagcc cagcagcccg aggccgcccg cgactagccc ccaccgtagt 1140atttatagtt aaattaaggg tgacagtaca ataaagtgat ggcgatgtaa aaaaaaaaaa 1200aaaaaaaaaa aaaaaaa 121724430DNAHomo sapiens 24gactgtcact cggtcccaga caccagagca agctcaagac ccagcagtgg gacagccaga 60cagacggcac gatggcactg agctcccaga tctgggccgc ttgcctcctg ctcctcctcc 120tcctcgccag cctgaccagt ggctctgttt tcccacaaca gacgggacaa cttgcagagc 180tgcaacccca ggacagagct ggagccaggg ccagctggat gcccatgttc cagaggcgaa 240ggaggcgaga cacccacttc cccatctgca ttttctgctg cggctgctgt catcgatcaa 300agtgtgggat gtgctgcaag acgtagaacc tacctgccct gcccccgtcc cctcccttcc 360ttatttattc ctgctgcccc agaacatagg tcttggaata aaatggctgg ttcttttgtt 420ttccaaaaaa 430252319DNAHomo sapiens 25ttccccactc ccccgccctc cccagggccc tgggaagggg ctcagcgtgg gaaaggatgg 60ttgagtttta accagaggca aagcgtgagc gggatcagtg tgtgcggaac gcaagcagcc 120gagagcggag aggcgccgct gtagttaact cctccctgcc cgccgcgccg accctcccca 180ggaaccccca gggagccagc atgaagcgag ctcaccccga gtacagctcc tcggacagcg 240agctggacga gaccatcgag gtggagaagg agagtgcgga cgagaatgga aacttgagtt 300cggctctagg ttccatgtcc ccaactacat cttcccagat tttggccaga aaaagacgga 360gaggaataat tgagaagcgc cgacgagacc ggatcaataa cagtttgtct gagctgagaa 420ggctggtacc cagtgctttt gagaagcagg gatctgctaa gctagaaaaa gccgagatcc 480tgcagatgac cgtggatcac ctgaaaatgc tgcatacggc aggagggaaa ggttactttg 540acgcgcacgc ccttgctatg gactatcgga gtttgggatt tcgggaatgc ctggcagaag 600ttgcgcgtta tctgagcatc attgaaggac tagatgcctc tgacccgctt cgagttcgac 660tggtttcgca tctcaacaac tacgcttccc agcgggaagc cgcgagcggc gcccacgcgg 720gcctcggaca cattccctgg gggaccgtct tcggacatca cccgcacatc gcgcacccgc 780tgttgctgcc ccagaacggc cacgggaacg cgggcaccac ggcctcaccc acggaaccgc 840accaccaggg caggctgggc tcggcacatc cggaggcgcc tgctttgcga gcgcccccta 900gcggcagcct cggaccggtg ctccctgtgg tcacctccgc ctccaaactg tcgccgcctc 960tgctctcctc agtggcctcc ctgtcggcct tccccttctc tttcggctcc ttccacttac 1020tgtctcccaa tgcactgagc ccttcagcac ccacgcaggc tgcaaacctt ggcaagccct 1080atagaccttg ggggacggag atcggagctt tttaaagaac tgatgtagaa tgagggaggg 1140gaaagtttaa aatcccagct gggctggact gttgccaaca tcaccttaaa gtcgtcagta 1200aaagtaaaaa ggaaaaaggt acactttcag ataatttttt ttttaaagac taaaggtttg 1260ttggtttact tttatctttt ttaatgtttt tttcatcatg tcatgtatta gcagttttta 1320aaaactagtt gttaaatttt gttcaagaca ttaaattgaa atagtgagta taagccaaca 1380ctttgtgata ggtttgtact gtgcctaatt tactttgtaa accagaatga ttccgttttt 1440gcctcaaaat ttggggaatc ttaacattta gtatttttgg tctgtttttc tccttgtata 1500gttatggtct gtttttagaa ttaattttcc aaaccactat gcttaatgtt aacatgattc 1560tgtttgttaa tattttgaca gattaaggtg ttgtataaat aatattcttt tggggggagg 1620ggaactatat tgaattttat atttctgagc aaagcgttga caaatcagat gatcagcttt 1680atccaagaaa gaagactagt aaattgtctg cctcctatag cagaaaggtg aatgtacaaa 1740ctgttggtgg ccctgaatcc atctgaccag ctgctggtat ctgccaggac tggcagttct 1800gatttagtta ggagagagcc gctgataggt taggtctcat ttggagtgtt ggtggaaagg 1860aaactgaagg taattgaata gaatacgcct gcatttacca gccccagcaa cacaaagaat 1920ttttaatcac acggatctca aattcacaaa tgttaacatg gataagtgat catggtgtgc 1980gagtggtcaa ttgagtagta cagtggaaac tgttaaatgc ataacctaat tttcctggga 2040ctgccatatt ttcttttaac tggaaatttt tatgtgagtt ttccttttgg tgcatggaac 2100tgtggttgcc aaggtattta aaagggcttt cctgcctcct tctctttgat ttatttaatt 2160tgatttgggc tataaaatat catttttcag gtttattctt ttagcaggtg tagttaaacg 2220acctccactg aactgggttt gacctctgtt gtactgatgt gttgtgacta aataaaaaag 2280aaagaacaaa gtaaaaaaaa aaaaaaaaaa aaaaaaaaa 2319264150DNAHomo sapiens 26cttgaatctt ggggcaggaa ctcagaaaac ttccagcccg ggcagcgcgc gcttggtgca 60agactcagga gctagcagcc cgtccccctc cgactctccg gtgccgccgc tgcctgctcc 120cgccacccta ggaggcgcgg tgccacccac tactctgtcc tctgcctgtg ctccgtgccc 180gaccctatcc cggcggagtc tccccatcct cctttgcttt ccgactgccc aaggcacttt 240caatctcaat ctcttctctc tctctctctc tctctctctc tctctctctc tctctctctc 300tctctctctc gcagggtggg gggaagagga ggaggaattc tttccccgcc taacatttca 360agggacacaa ttcactccaa gtctcttccc tttccaagcc gcttccgaag tgctcccggt 420gcccgcaact cctgatccca acccgcgaga ggagcctctg cgacctcaaa gcctctcttc 480cttctccctc gcttccctcc tcctcttgct acctccacct ccaccgccac ctccacctcc 540ggcacccacc caccgccgcc gccgccaccg gcagcgcctc ctcctctcct cctcctcctc 600ccctcttctc tttttggcag ccgctggacg tccggtgttg atggtggcag cggcggcagc 660ctaagcaaca gcagccctcg cagcccgcca gctcgcgctc gccccgccgg cgtccccagc 720cctatcacct catctcccga aaggtgctgg gcagctccgg ggcggtcgag gcgaagcggc 780tgcagcggcg gtagcggcgg cgggaggcag gatgagcgca cgcggtgagg gcgcggggca 840gccgtccact tcagcccagg gacaacctgc cgccccagcg cctcagaaga gaggacgcgg 900ccgccccagg aagcagcagc aagaaccaac cggtgagccc tctcctaaga gacccagggg 960aagacccaaa ggcagcaaaa acaagagtcc ctctaaagca gctcaaaaga aagcagaagc 1020cactggagaa aaacggccaa gaggcagacc taggaaatgg ccacaacaag ttgttcagaa 1080gaagcctgct caggaggaaa ctgaagagac atcctcacaa gagtctgccg aagaggacta 1140gggggcgcca acgttcgatt tctacctcag cagcagttgg atcttttgaa gggagaagac 1200actgcagtga ccacttattc tgtattgcca tggtctttcc actttcatct ggggtggggt 1260ggggtggggt gggggagggg ggggtggggt ggggagaaat cacataacct taaaaaggac 1320tatattaatc accttctttg taatcccttc acagtcccag gtttagtgaa aaactgctgt 1380aaacacaggg gacacagctt aacaatgcaa cttttaatta ctgttttctt ttttcttaac 1440ctactaatag tttgttgatc tgataagcaa gagtgggcgg gtgagaaaaa ccgaattggg 1500tttagtcaat cactgcactg catgcaaaca agaaacgtgt cacacttgtg acgtcgggca 1560ttcatatagg aagaacgcgg tgtgtaacac tgtgtacacc tcaaatacca ccccaaccca 1620ctccctgtag tgaatcctct gtttagaaca ccaaagataa ggactagata ctactttctc 1680tttttcgtat aatcttgtag acacttactt gatgattttt aactttttat ttctaaatga 1740gacgaaatgc tgatgtatcc tttcattcag ctaacaaact agaaaaggtt atgttcattt 1800ttcaaaaagg gaagtaagca aacaaatatt gccaactctt ctatttatgg atatcacaca 1860tatcagcagg agtaataaat ttactcacag cacttgtttt caggacaaca cttcattttc 1920aggaaatcta cttcctacag agccaaaatg ccatttagca ataaataaca cttgtcagcc 1980tcagagcatt taaggaaact agacaagtaa aattatcctc tttgtaattt aatgaaaagg 2040tacaacagaa taatgcatga tgaactcacc taattatgag gtgggaggag cgaaatctaa 2100atttcttttg ctatagttat acatcaattt aaaaagcaaa aaaaaaaaag gggggggcaa 2160tctctctctg tgtctttctc tctctctctt cctctccctc tctcttttca ttgtgtatca 2220gtttccatga aagacctgaa taccacttac ctcaaattaa gcatatgtgt tacttcaagt 2280aatacgtttt gacataagat ggttgaccaa ggtgcttttc ttcggcttga gttcaccatc 2340tcttcattca aactgcactt ttagccagag atgcaatata tccccactac tcaatactac 2400ctctgaatgt tacaacgaat ttacagtcta gtacttatta catgctgcta tacacaagca 2460atgcaagaaa aaaacttact gggtaggtga ttctaatcat ctgcagttct ttttgtacac 2520ttaattacag ttaaagaagc aatctcctta ctgtgtttca gcatgactat gtatttttct 2580atgttttttt aattaaaaat ttttaaaata cttgtttcag cttctctgct agatttctac 2640attaacttga aaatttttta accaagtcgc tcctaggttc ttaaggataa ttttcctcaa 2700tcacactaca catcacacaa gatttgactg taatatttaa atattaccct ccaagtctgt 2760acctcaaatg aattctttaa ggagatggac taattgactt gcaaagacct acctccagac 2820ttcaaaagga atgaacttgt tacttgcagc attcatttgt tttttcaatg tttgaaatag 2880ttcaaactgc agctaaccct agtcaaaact atttttgtaa aagacatttg atagaaagga 2940acacgttttt acatactttt gcaaaataag taaataataa ataaaataaa agccaacctt 3000caaagaaact tgaagctttg taggtgagat gcaacaagcc ctgcttttgc ataatgcaat 3060caaaaatatg tgtttttaag attagttgaa tataagaaaa tgcttgacaa atattttcat 3120gtattttaca caaatgtgat ttttgtaata tgtctcaacc agatttattt taaacgcttc 3180ttatgtagag tttttatgcc tttctctcct agtgagtgtg ctgacttttt aacatggtat 3240tatcaactgg gccaggaggt agtttctcat gacggctttt gtcagtatgg cttttagtac 3300tgaagccaaa tgaaactcaa aaccatctct cttccagctg cttcagggag gtagtttcaa 3360aggccacata cctctctgag actggcagat cgctcactgt tgtgaatcac caaaggagct 3420atggagagaa ttaaaactca acattactgt taactgtgcg ttaaataagc aaataaacag 3480tggctcataa aaataaaagt cgcattccat atctttggat gggcctttta gaaacctcat 3540tggccagctc ataaaatgga agcaattgct catgttggcc aaacatggtg caccgagtga 3600tttccatctc tggtaaagtt acacttttat ttcctgtatg ttgtacaatc aaaacacact 3660actacctctt aagtcccagt atacctcatt tttcatactg aaaaaaaaag cttgtggcca 3720atggaacagt aagaacatca taaaattttt atatatatag tttatttttg tgggagataa 3780attttatagg actgttcttt gctgttgttg gtcgcagcta cataagactg gacatttaac 3840ttttctacca tttctgcaag ttaggtatgt ttgcaggaga aaagtatcaa gacgtttaac 3900tgcagttgac tttctccctg ttcctttgag tgtcttctaa ctttattctt tgttctttat 3960gtagaattgc tgtctatgat tgtactttga atcgcttgct tgttgaaaat atttctctag 4020tgtattatca ctgtctgttc tgcacaataa acataacagc ctctgtgatc cccatgtgtt 4080ttgattcctg ctctttgtta cagttccatt aaatgagtaa taaagtttgg tcaaaacaga 4140aaaaaaaaaa 4150271595DNAHomo sapiens 27gagtgagtga gagggcagag gaaatactca atctgtgcca ctcactgcct tgagcctgct 60tcctcactcc aggactgcca gaggaagcaa tcaccaaaat gaagactgct ttaattttgc 120tcagcatttt gggaatggcc tgtgctttct caatgaaaaa tttgcatcga agagtcaaaa 180tagaggattc tgaagaaaat ggggtcttta agtacaggcc acgatattat ctttacaagc 240atgcctactt ttatcctcat ttaaaacgat ttccagttca gggcagtagt gactcatccg 300aagaaaatgg agatgacagt tcagaagagg aggaggaaga agaggagact tcaaatgaag 360gagaaaacaa tgaagaatcg aatgaagatg aagactctga ggctgagaat accacacttt 420ctgctacaac actgggctat ggagaggacg ccacgcctgg cacagggtat acagggttag 480ctgcaatcca gcttcccaag aaggctgggg atataacaaa taaagctaca aaagagaagg 540aaagtgatga agaagaagag gaggaagagg aaggaaatga aaacgaagaa agcgaagcag 600aagtggatga aaacgaacaa ggcataaacg gcaccagtac caacagcaca gaggcagaaa 660acggcaacgg cagcagcgga ggagacaatg gagaagaagg ggaagaagaa agtgtcactg 720gagccaatgc agaagacacc acagagaccg gaaggcaggg caagggcacc tcgaagacaa 780caacctctcc aaatggtggg tttgaaccta caaccccacc acaagtctat agaaccactt 840ccccaccttt tgggaaaacc accaccgttg aatacgaggg ggagtacgaa tacacgggcg 900ccaatgaata cgacaatgga tatgaaatct atgaaagtga gaacggggaa cctcgtgggg 960acaattaccg agcctatgaa gatgagtaca gctactttaa aggacaaggc tacgatggct 1020atgatggtca gaattactac caccaccagt gaagctccag cctgggatga attcatccat 1080tctggctttg catccggcta ccattttcga agttcaactc aggaaggtgc aatataacaa 1140atgtgcatat tataatgagg aatggtacta ccgttccaga ttttctgtaa ttgcttctgc 1200aaagtaatag gcttcttgtc cctttttttt ctggcatgtt atggaatgat cattgtaaat 1260caggaccatt tatcaagcag tacaccaact cataagatca aatttcattg aatggtttga 1320ggttgtagct ctataaatag tagtttttaa catgcctgta gtattgctaa ctgcaaaaac 1380atactctttg tacaagaagt gcttctaaga atttcattga cattaatgac actgtataca 1440ataaatgtgt agtttcttaa tcgcactacc tatgcaacac tgtgtattag gtttatcatc 1500ctcatgtatt tttatgtgac ctgtatgtat attctaatct acgagtttta tcacaaataa 1560aaatgcaatc cttcaaatgt gttataatta aaaaa 1595281000DNAHomo sapiens 28actctcattc cacgttctta actgttccat tttccgtatc tgcttcgggc ttccacctca 60tttttttcgc tttgcccatt ctgtttcagc cagtcgccaa gaatcatgaa agtcgccagt 120ggcagcaccg ccaccgccgc cgcgggcccc agctgcgcgc tgaaggccgg caagacagcg 180agcggtgcgg gcgaggtggt gcgctgtctg tctgagcaga gcgtggccat ctcgcgctgc 240gccgggggcg ccggggcgcg cctgcctgcc ctgctggacg agcagcaggt aaacgtgctg 300ctctacgaca tgaacggctg ttactcacgc ctcaaggagc tggtgcccac cctgccccag 360aaccgcaagg tgagcaaggt ggagattctc cagcacgtca tcgactacat cagggacctt 420cagttggagc tgaactcgga atccgaagtt ggaacccccg ggggccgagg gctgccggtc 480cgggctccgc tcagcaccct caacggcgag atcagcgccc tgacggccga ggcggcatgc 540gttcctgcgg acgatcgcat cttgtgtcgc tgaagcgcct cccccaggga ccggcggacc 600ccagccatcc agggggcaag aggaattacg tgctctgtgg gtctccccca acgcgcctcg 660ccggatctga gggagaacaa gaccgatcgg cggccactgc gcccttaact gcatccagcc 720tggggctgag gctgaggcac tggcgaggag agggcgctcc tctctgcaca cctactagtc 780accagagact ttagggggtg ggattccact cgtgtgtttc tattttttga aaagcagaca 840ttttaaaaaa tggtcacgtt tggtgcttct cagatttctg aggaaattgc tttgtattgt 900atattacaat gatcaccgac tgaaaatatt gttttacaat agttctgtgg ggctgttttt 960ttgttattaa acaaataatt tagatggtgg taaaaaaaaa 1000291402DNAHomo sapiens 29ggggacgaag ggaagctcca gcgtgtggcc ccggcgagtg cggataaaag ccgccccgcc 60gggctcgggc ttcattctga gccgagcccg gtgccaagcg cagctagctc agcaggcggc 120agcggcggcc tgagcttcag ggcagccagc tccctcccgg tctcgccttc cctcgcggtc 180agcatgaaag ccttcagtcc cgtgaggtcc gttaggaaaa acagcctgtc ggaccacagc 240ctgggcatct cccggagcaa aacccctgtg gacgacccga tgagcctgct atacaacatg 300aacgactgct actccaagct caaggagctg gtgcccagca tcccccagaa caagaaggtg 360agcaagatgg aaatcctgca gcacgtcatc gactacatct tggacctgca gatcgccctg 420gactcgcatc ccactattgt cagcctgcat caccagagac ccgggcagaa ccaggcgtcc 480aggacgccgc tgaccaccct caacacggat atcagcatcc tgtccttgca ggcttctgaa 540ttcccttctg agttaatgtc aaatgacagc aaagcactgt gtggctgaat aagcggtgtt 600catgatttct tttattcttt gcacaacaac aacaacaaca aattcacgga atcttttaag 660tgctgaactt atttttcaac catttcacaa ggaggacaag ttgaatggac ctttttaaaa 720agaaaaaaaa aatggaagga aaactaagaa tgatcatctt cccagggtgt tctcttactt 780ggactgtgat attcgttatt tatgaaaaag acttttaaat gccctttctg cagttggaag 840gttttcttta tatactattc ccaccatggg gagcgaaaac gttaaaatca caaggaattg 900cccaatctaa gcagactttg ccttttttca aaggtggagc gtgaatacca gaaggatcca 960gtattcagtc acttaaatga agtcttttgg tcagaaatta cctttttgac acaagcctac 1020tgaatgctgt gtatatattt atatataaat atatctattt gagtgaaacc ttgtgaactc 1080tttaattaga gttttcttgt atagtggcag agatgtctat ttctgcattc aaaagtgtaa 1140tgatgtactt attcatgcta aactttttat aaaagtttag ttgtaaactt aaccctttta 1200tacaaaataa atcaagtgtg tttattgaat ggtgattgcc tgctttattt cagaggacca 1260gtgctttgat ttttattatg ctatgttata actgaaccca aataaataca agttcaaatt 1320tatgtagact gtataagatt ataataaaac atgtctgaag tcaaaaaaaa aaaaaaaaaa 1380aaaaaaaaaa aaaaaaaaaa aa 1402301252DNAHomo sapiens 30gatctggggt gctgccagga aaaagcaaat tctggaagtt aatggttttg agtgattttt 60aaatccttgc tggcggagag gcccgcctct ccccggtatc agcgcttcct cattctttga 120atccgcggct ccgcggtctt cggcgtcaga ccagccggag gaagcctgtt tgcaatttaa 180gcgggctgtg aacgcccagg gccggcgggg gcagggccga ggcgggccat tttgaataaa 240gaggcgtgcc ttccaggcag gctctataag tgaccgccgc ggcgagcgtg cgcgcgttgc 300aggtcactgt agcgggactt cttttggttt tctttctctt tggggcacct ctggactcac 360tccccagcat gaaggcgctg agcccggtgc gcggctgcta cgaggcggtg tgctgcctgt 420cggaacgcag tctggccatc gcccggggcc gagggaaggg cccggcagct gaggagccgc 480tgagcttgct ggacgacatg aaccactgct actcccgcct gcgggaactg gtacccggag 540tcccgagagg cactcagctt agccaggtgg aaatcctaca gcgcgtcatc gactacattc

600tcgacctgca ggtagtcctg gccgagccag cccctggacc ccctgatggc ccccaccttc 660ccatccagac agccgagctc actccggaac ttgtcatctc caacgacaaa aggagctttt 720gccactgact cggccgtgtc ctgacacctc cagaacgcag gtgctggcgc ccgttctgcc 780tgggaccccg ggaacctctc ctgccggaag ccggacggca gggatgggcc ccaacttcgc 840cctgcccact tgacttcacc aaatcccttc ctggagacta aacctggtgc tcaggagcga 900aggactgtga acttgtggcc tgaagagcca gagctagctc tggccaccag ctgggcgacg 960tcaccctgct cccaccccac ccccaagttc taaggtctct tcagagcgtg gaggtgtgga 1020aggagtggct gctctccaaa ctatgccaag gcggcggcag agctggtctt ctggtctcct 1080tggagaaagg ttctgttgcc ctgatttatg aactctataa tagagtatat aggttttgta 1140ccttttttac aggaaggtga ctttctgtaa caatgcgatg tatattaaac tttttataaa 1200agttaacatt ttgcataata aacgattttt aaacacttga aaaaaaaaaa aa 1252312381DNAHomo sapiens 31actgccgcgg ccctgctgct cagggcacat gcctcccctc cccaggccgc ggcccagctg 60accctcgggg ctcccccggc agcggacagg gaagggttaa aggcccccgg ctccctgccc 120cctgccctgg ggaacccctg gccctgtggg gacatgaact gtgtttgccg cctggtcctg 180gtcgtgctga gcctgtggcc agatacagct gtcgcccctg ggccaccacc tggcccccct 240cgagtttccc cagaccctcg ggccgagctg gacagcaccg tgctcctgac ccgctctctc 300ctggcggaca cgcggcagct ggctgcacag ctgagggaca aattcccagc tgacggggac 360cacaacctgg attccctgcc caccctggcc atgagtgcgg gggcactggg agctctacag 420ctcccaggtg tgctgacaag gctgcgagcg gacctactgt cctacctgcg gcacgtgcag 480tggctgcgcc gggcaggtgg ctcttccctg aagaccctgg agcccgagct gggcaccctg 540caggcccgac tggaccggct gctgcgccgg ctgcagctcc tgatgtcccg cctggccctg 600ccccagccac ccccggaccc gccggcgccc ccgctggcgc ccccctcctc agcctggggg 660ggcatcaggg ccgcccacgc catcctgggg gggctgcacc tgacacttga ctgggccgtg 720aggggactgc tgctgctgaa gactcggctg tgacccgggg cccaaagcca ccaccgtcct 780tccaaagcca gatcttattt atttatttat ttcagtactg ggggcgaaac agccaggtga 840tccccccgcc attatctccc cctagttaga gacagtcctt ccgtgaggcc tggggggcat 900ctgtgcctta tttatactta tttatttcag gagcaggggt gggaggcagg tggactcctg 960ggtccccgag gaggagggga ctggggtccc ggattcttgg gtctccaaga agtctgtcca 1020cagacttctg ccctggctct tccccatcta ggcctgggca ggaacatata ttatttattt 1080aagcaattac ttttcatgtt ggggtgggga cggaggggaa agggaagcct gggtttttgt 1140acaaaaatgt gagaaacctt tgtgagacag agaacaggga attaaatgtg tcatacatat 1200ccacttgagg gcgatttgtc tgagagctgg ggctggatgc ttgggtaact ggggcagggc 1260aggtggaggg gagacctcca ttcaggtgga ggtcccgagt gggcggggca gcgactggga 1320gatgggtcgg tcacccagac agctctgtgg aggcagggtc tgagccttgc ctggggcccc 1380gcactgcata gggccttttg tttgtttttt gagatggagt ctcgctctgt tgcctaggct 1440ggagtgcagt gaggcaatct gaggtcactg caacctccac ctcccgggtt caagcaattc 1500tcctgcctca gcctcccgat tagctgggat cacaggtgtg caccaccatg cccagctaat 1560tatttatttc ttttgtattt ttagtagaga cagggtttca ccatgttggc caggctggtt 1620tcgaactcct gacctcaggt gatcctcctg cctcggcctc ccaaagtgct gggattacag 1680gtgtgagcca ccacacctga cccataggtc ttcaataaat atttaatgga aggttccaca 1740agtcaccctg tgatcaacag tacccgtatg ggacaaagct gcaaggtcaa gatggttcat 1800tatggctgtg ttcaccatag caaactggaa acaatctaga tatccaacag tgagggttaa 1860gcaacatggt gcatctgtgg atagaacgcc acccagccgc ccggagcagg gactgtcatt 1920cagggaggct aaggagagag gcttgcttgg gatatagaaa gatatcctga cattggccag 1980gcatggtggc tcacgcctgt aatcctggca ctttgggagg acgaagcgag tggatcactg 2040aagtccaaga gttcgagacc ggcctgcgag acatggcaaa accctgtctc aaaaaagaaa 2100gaatgatgtc ctgacatgaa acagcaggct acaaaaccac tgcatgctgt gatcccaatt 2160ttgtgttttt ctttctatat atggattaaa acaaaaatcc taaagggaaa tacgccaaaa 2220tgttgacaat gactgtctcc aggtcaaagg agagaggtgg gattgtgggt gacttttaat 2280gtgtatgatt gtctgtattt tacagaattt ctgccatgac tgtgtatttt gcatgacaca 2340ttttaaaaat aataaacact atttttagaa taacagaaaa a 2381321201DNAHomo sapiens 32aatattagag tctcaacccc caataaatat aggactggag atgtctgagg ctcattctgc 60cctcgagccc accgggaacg aaagagaagc tctatctccc ctccaggagc ccagctatga 120actccttctc cacaagcgcc ttcggtccag ttgccttctc cctggggctg ctcctggtgt 180tgcctgctgc cttccctgcc ccagtacccc caggagaaga ttccaaagat gtagccgccc 240cacacagaca gccactcacc tcttcagaac gaattgacaa acaaattcgg tacatcctcg 300acggcatctc agccctgaga aaggagacat gtaacaagag taacatgtgt gaaagcagca 360aagaggcact ggcagaaaac aacctgaacc ttccaaagat ggctgaaaaa gatggatgct 420tccaatctgg attcaatgag gagacttgcc tggtgaaaat catcactggt cttttggagt 480ttgaggtata cctagagtac ctccagaaca gatttgagag tagtgaggaa caagccagag 540ctgtgcagat gagtacaaaa gtcctgatcc agttcctgca gaaaaaggca aagaatctag 600atgcaataac cacccctgac ccaaccacaa atgccagcct gctgacgaag ctgcaggcac 660agaaccagtg gctgcaggac atgacaactc atctcattct gcgcagcttt aaggagttcc 720tgcagtccag cctgagggct cttcggcaaa tgtagcatgg gcacctcaga ttgttgttgt 780taatgggcat tccttcttct ggtcagaaac ctgtccactg ggcacagaac ttatgttgtt 840ctctatggag aactaaaagt atgagcgtta ggacactatt ttaattattt ttaatttatt 900aatatttaaa tatgtgaagc tgagttaatt tatgtaagtc atatttatat ttttaagaag 960taccacttga aacattttat gtattagttt tgaaataata atggaaagtg gctatgcagt 1020ttgaatatcc tttgtttcag agccagatca tttcttggaa agtgtaggct tacctcaaat 1080aaatggctaa cttatacata tttttaaaga aatatttata ttgtatttat ataatgtata 1140aatggttttt ataccaataa atggcatttt aaaaaattca gcaaaaaaaa aaaaaaaaaa 1200a 1201335294DNAHomo sapiens 33ctagggcatg gcatcccacg tgggtgtcag cacggccgca gaagaaccac ttctctggcc 60cacccatgcc tgctaggcca tgcttcttca gaagtggcca caactctcct gacgtctcca 120gagccggtca ttccacccag ggggacttca gctgccactg gacacttcaa ttgtacgctg 180cgaccagttg ccaggaagga gagggctggc aagagagccg cggcagccgt ggcagggtgt 240aggggacggt ggacggccag ggcccccccc tctctctctt tctctctctc tctcttgctt 300ggtttctgta atgaggaagt tctccgcagc tcagtttcct ttccctcact gagcgcctga 360aacaggaagt cagtcagtta agctggtggc agcagccgag gccaccaaga ggcaacgggc 420ggcaggttgc agtggagggg cctccgctcc cctcggtggt gtgtgggtcc tgggggtgcc 480tgccggcccg gccgaggagg cccacgccca ccatggtccc ctgctggaac catggcaaca 540tcacccgctc caaggcggag gagctgcttt ccaggacagg caaggacggg agcttcctcg 600tgcgtgccag cgagtccatc tcccgggcat acgcgctctg cgtgctgtat cggaattgcg 660tttacactta cagaattctg cccaatgaag atgataaatt cactgttcag gcatccgaag 720gcgtctccat gaggttcttc accaagctgg accagctcat cgagttttac aagaaggaaa 780acatggggct ggtgacccat ctgcaatacc ctgtgccgct ggaggaagag gacacaggcg 840acgaccctga ggaggacaca gtagaaagtg tcgtgtctcc acccgagctg cccccaagaa 900acatcccgct gactgccagc tcctgtgagg ccaaggaggt tcctttttca aacgagaatc 960cccgagcgac cgagaccagc cggccgagcc tctccgagac attgttccag cgactgcaaa 1020gcatggacac cagtgggctt ccagaagagc atcttaaggc catccaagat tatttaagca 1080ctcagctcgc ccaggactct gaatttgtga agacagggtc cagcagtctt cctcacctga 1140agaaactgac cacactgctc tgcaaggagc tctatggaga agtcatccgg accctcccat 1200ccctggagtc tctgcagagg ttatttgacc agcagctctc cccgggcctc cgtccacgtc 1260ctcaggttcc tggtgaggcc aatcccatca acatggtgtc caagctcagc caactgacaa 1320gcctgttgtc gtccattgaa gacaaggtca aggccttgct gcacgagggt cctgagtctc 1380cgcaccggcc ctcccttatc cctccagtca cctttgaggt gaaggcagag tctctgggga 1440ttcctcagaa aatgcagctc aaagtcgacg ttgagtctgg gaaactgatc attaagaagt 1500ccaaggatgg ttctgaggac aagttctaca gccacaagaa aatcctgcag ctcattaagt 1560cacagaaatt tctgaataag ttggtgatct tggtggaaac agagaaggag aagatcctgc 1620ggaaggaata tgtttttgct gactccaaaa agagagaagg cttctgccag ctcctgcagc 1680agatgaagaa caagcactca gagcagccgg agcccgacat gatcaccatc ttcatcggca 1740cctggaacat gggtaacgcc ccccctccca agaagatcac gtcctggttt ctctccaagg 1800ggcagggaaa gacgcgggac gactctgcgg actacatccc ccatgacatt tacgtgatcg 1860gcacccaaga ggaccccctg agtgagaagg agtggctgga gatcctcaaa cactccctgc 1920aagaaatcac cagtgtgact tttaaaacag tcgccatcca cacgctctgg aacatccgca 1980tcgtggtgct ggccaagcct gagcacgaga accggatcag ccacatctgt actgacaacg 2040tgaagacagg cattgcaaac acactgggga acaagggagc cgtgggggtg tcgttcatgt 2100tcaatggaac ctccttaggg ttcgtcaaca gccacttgac ttcaggaagt gaaaagaaac 2160tcaggcgaaa ccaaaactat atgaacattc tccggttcct ggccctgggc gacaagaagc 2220tgagtccctt taacatcact caccgcttca cgcacctctt ctggtttggg gatcttaact 2280accgtgtgga tctgcctacc tgggaggcag aaaccatcat ccagaaaatc aagcagcagc 2340agtacgcaga cctcctgtcc cacgaccagc tgctcacaga gaggagggag cagaaggtct 2400tcctacactt cgaggaggaa gaaatcacgt ttgccccaac ctaccgtttt gagagactga 2460ctcgggacaa atacgcctac accaagcaga aagcgacagg gatgaagtac aacttgcctt 2520cctggtgtga ccgagtcctc tggaagtctt atcccctggt gcacgtggtg tgtcagtctt 2580atggcagtac cagcgacatc atgacgagtg accacagccc tgtctttgcc acatttgagg 2640caggagtcac ttcccagttt gtctccaaga acggtcccgg gactgttgac agccaaggac 2700agattgagtt tctcaggtgc tatgccacat tgaagaccaa gtcccagacc aaattctacc 2760tggagttcca ctcgagctgc ttggagagtt ttgtcaagag tcaggaagga gaaaatgaag 2820aaggaagtga gggggagctg gtggtgaagt ttggtgagac tcttccaaag ctgaagccca 2880ttatctctga ccctgagtac ctgctagacc agcacatcct catcagcatc aagtcctctg 2940acagcgacga atcctatggc gagggctgca ttgcccttcg gttagaggcc acagaaacgc 3000agctgcccat ctacacgcct ctcacccacc atggggagtt gacaggccac ttccaggggg 3060agatcaagct gcagacctct cagggcaaga cgagggagaa gctctatgac tttgtgaaga 3120cggagcgtga tgaatccagt gggccaaaga ccctgaagag cctcaccagc cacgacccca 3180tgaagcagtg ggaagtcact agcagggccc ctccgtgcag tggctccagc atcactgaaa 3240tcatcaaccc caactacatg ggagtggggc cctttgggcc accaatgccc ctgcacgtga 3300agcagacctt gtcccctgac cagcagccca cagcctggag ctacgaccag ccgcccaagg 3360actccccgct ggggccctgc aggggagaaa gtcctccgac acctcccggc cagccgccca 3420tatcacccaa gaagttttta ccctcaacag caaaccgggg tctccctccc aggacacagg 3480agtcaaggcc cagtgacctg gggaagaacg caggggacac gctgcctcag gaggacctgc 3540cgctgacgaa gcccgagatg tttgagaacc ccctgtatgg gtccctgagt tccttcccta 3600agcctgctcc caggaaggac caggaatccc ccaaaatgcc gcggaaggaa cccccgccct 3660gcccggaacc cggcatcttg tcgcccagca tcgtgctcac caaagcccag gaggctgatc 3720gcggcgaggg gcccggcaag caggtgcccg cgccccggct gcgctccttc acgtgctcat 3780cctctgccga gggcagggcg gccggcgggg acaagagcca agggaagccc aagaccccgg 3840tcagctccca ggccccggtg ccggccaaga ggcccatcaa gccttccaga tcggaaatca 3900accagcagac cccgcccacc ccgacgccgc ggccgccgct gccagtcaag agcccggcgg 3960tgctgcacct ccagcactcc aagggccgcg actaccgcga caacaccgag ctcccgcatc 4020acggcaagca ccggccggag gaggggccac cagggcctct aggcaggact gccatgcagt 4080gaagccctca gtgagctgcc actgagtcgg gagcccagag gaacggcgtg aagccactgg 4140accctctccc gggacctcct gctggctcct cctgcccagc ttcctatgca aggctttgtg 4200ttttcaggaa agggcctagc ttctgtgtgg cccacagagt tcactgcctg tgagacttag 4260caccaagtgc tgaggctgga agaaaaacgc acaccagacg ggcaacaaac agtctgggtc 4320cccagctcgc tcttggtact tgggacccca gtgcctcgtt gagggcgcca ttctgaagaa 4380aggaactgca gcgccgattt gagggtggag atatagataa taataatatt aataataata 4440atggccacat ggatcgaaca ctcatgatgt gccaagtgct gtgctaagtg ctttacgaac 4500attcgtcata tcaggatgac ctcgagagct gaggctctag ccacctaaaa ccacgtgccc 4560aaacccacca gtttaaaacg gtgtgtgttc ggaggggtga aagcattaag aagcccagtg 4620ccctcctgga gtgagacaag ggctcggcct taaggagctg aagagtctgg gtagcttgtt 4680tagggtacaa gaagcctgtt ctgtccagct tcagtgacac aagctgcttt agctaaagtc 4740ccgcgggttc cggcatggct aggctgagag cagggatcta cctggcttct cagttctttg 4800gttggaagga gcaggaaatc agctcctatt ctccagtgga gagatctggc ctcagcttgg 4860gctagagatg ccaaggcctg tgccaggttc cctgtgccct cctcgaggtg ggcagccatc 4920accagccaca gttaagccaa gccccccaac atgtattcca tcgtgctggt agaagagtct 4980ttgctgttgc tcccgaaagc cgtgctctcc agcctggctg ccagggaggg tgggcctctt 5040ggttccaggc tcttgaaata gtgcagcctt ttcttcctat ctctgtggct ttcagctctg 5100cttccttggt tattaggaga atagatgggt gatgtctttc cttatgttgc tttttcaaca 5160tagcagaatt aatgtaggga gctaaatcca gtggtgtgtg tgaatgcaga agggaatgca 5220ccccacattc ccatgatgga agtctgcgta accaataaat tgtgcctttc tcactcaaaa 5280aaaaaaaaaa aaaa 5294343879DNAHomo sapiens 34atcagacgcg cagaggaggc ggggccgcgg ctggtttcct gccggggggc ggctctgggc 60cgccgagtcc cctcctcccg cccctgagga ggaggagccg ccgccacccg ccgcgcccga 120cacccgggag gccccgccag cccgcgggag aggcccagcg ggagtcgcgg aacagcaggc 180ccgagcccac cgcgccgggc cccggacgcc gcgcggaaaa gatgaattta caaccaattt 240tctggattgg actgatcagt tcagtttgct gtgtgtttgc tcaaacagat gaaaatagat 300gtttaaaagc aaatgccaaa tcatgtggag aatgtataca agcagggcca aattgtgggt 360ggtgcacaaa ttcaacattt ttacaggaag gaatgcctac ttctgcacga tgtgatgatt 420tagaagcctt aaaaaagaag ggttgccctc cagatgacat agaaaatccc agaggctcca 480aagatataaa gaaaaataaa aatgtaacca accgtagcaa aggaacagca gagaagctca 540agccagagga tattactcag atccaaccac agcagttggt tttgcgatta agatcagggg 600agccacagac atttacatta aaattcaaga gagctgaaga ctatcccatt gacctctact 660accttatgga cctgtcttac tcaatgaaag acgatttgga gaatgtaaaa agtcttggaa 720cagatctgat gaatgaaatg aggaggatta cttcggactt cagaattgga tttggctcat 780ttgtggaaaa gactgtgatg ccttacatta gcacaacacc agctaagctc aggaaccctt 840gcacaagtga acagaactgc accagcccat ttagctacaa aaatgtgctc agtcttacta 900ataaaggaga agtatttaat gaacttgttg gaaaacagcg catatctgga aatttggatt 960ctccagaagg tggtttcgat gccatcatgc aagttgcagt ttgtggatca ctgattggct 1020ggaggaatgt tacacggctg ctggtgtttt ccacagatgc cgggtttcac tttgctggag 1080atgggaaact tggtggcatt gttttaccaa atgatggaca atgtcacctg gaaaataata 1140tgtacacaat gagccattat tatgattatc cttctattgc tcaccttgtc cagaaactga 1200gtgaaaataa tattcagaca atttttgcag ttactgaaga atttcagcct gtttacaagg 1260agctgaaaaa cttgatccct aagtcagcag taggaacatt atctgcaaat tctagcaatg 1320taattcagtt gatcattgat gcatacaatt ccctttcctc agaagtcatt ttggaaaacg 1380gcaaattgtc agaaggcgta acaataagtt acaaatctta ctgcaagaac ggggtgaatg 1440gaacagggga aaatggaaga aaatgttcca atatttccat tggagatgag gttcaatttg 1500aaattagcat aacttcaaat aagtgtccaa aaaaggattc tgacagcttt aaaattaggc 1560ctctgggctt tacggaggaa gtagaggtta ttcttcagta catctgtgaa tgtgaatgcc 1620aaagcgaagg catccctgaa agtcccaagt gtcatgaagg aaatgggaca tttgagtgtg 1680gcgcgtgcag gtgcaatgaa gggcgtgttg gtagacattg tgaatgcagc acagatgaag 1740ttaacagtga agacatggat gcttactgca ggaaagaaaa cagttcagaa atctgcagta 1800acaatggaga gtgcgtctgc ggacagtgtg tttgtaggaa gagggataat acaaatgaaa 1860tttattctgg caaattctgc gagtgtgata atttcaactg tgatagatcc aatggcttaa 1920tttgtggagg aaatggtgtt tgcaagtgtc gtgtgtgtga gtgcaacccc aactacactg 1980gcagtgcatg tgactgttct ttggatacta gtacttgtga agccagcaac ggacagatct 2040gcaatggccg gggcatctgc gagtgtggtg tctgtaagtg tacagatccg aagtttcaag 2100ggcaaacgtg tgagatgtgt cagacctgcc ttggtgtctg tgctgagcat aaagaatgtg 2160ttcagtgcag agccttcaat aaaggagaaa agaaagacac atgcacacag gaatgttcct 2220attttaacat taccaaggta gaaagtcggg acaaattacc ccagccggtc caacctgatc 2280ctgtgtccca ttgtaaggag aaggatgttg acgactgttg gttctatttt acgtattcag 2340tgaatgggaa caacgaggtc atggttcatg ttgtggagaa tccagagtgt cccactggtc 2400cagacatcat tccaattgta gctggtgtgg ttgctggaat tgttcttatt ggccttgcat 2460tactgctgat atggaagctt ttaatgataa ttcatgacag aagggagttt gctaaatttg 2520aaaaggagaa aatgaatgcc aaatgggaca cgggtgaaaa tcctatttat aagagtgccg 2580taacaactgt ggtcaatccg aagtatgagg gaaaatgagt actgcccgtg caaatcccac 2640aacactgaat gcaaagtagc aatttccata gtcacagtta ggtagcttta gggcaatatt 2700gccatggttt tactcatgtg caggttttga aaatgtacaa tatgtataat ttttaaaatg 2760ttttattatt ttgaaaataa tgttgtaatt catgccaggg actgacaaaa gacttgagac 2820aggatggtta ctcttgtcag ctaaggtcac attgtgcctt tttgaccttt tcttcctgga 2880ctattgaaat caagcttatt ggattaagtg atatttctat agcgattgaa agggcaatag 2940ttaaagtaat gagcatgatg agagtttctg ttaatcatgt attaaaactg atttttagct 3000ttacaaatat gtcagtttgc agttatgcag aatccaaagt aaatgtcctg ctagctagtt 3060aaggattgtt ttaaatctgt tattttgcta tttgcctgtt agacatgact gatgacatat 3120ctgaaagaca agtatgttga gagttgctgg tgtaaaatac gtttgaaata gttgatctac 3180aaaggccatg ggaaaaattc agagagttag gaaggaaaaa ccaatagctt taaaacctgt 3240gtgccatttt aagagttact taatgtttgg taacttttat gccttcactt tacaaattca 3300agccttagat aaaagaaccg agcaattttc tgctaaaaag tccttgattt agcactattt 3360acatacaggc catactttac aaagtatttg ctgaatgggg accttttgag ttgaatttat 3420tttattattt ttattttgtt taatgtctgg tgctttctgt cacctcttct aatcttttaa 3480tgtatttgtt tgcaattttg gggtaagact ttttttatga gtactttttc tttgaagttt 3540tagcggtcaa tttgcctttt taatgaacat gtgaagttat actgtggcta tgcaacagct 3600ctcacctacg cgagtcttac tttgagttag tgccataaca gaccactgta tgtttacttc 3660tcaccatttg agttgcccat cttgtttcac actagtcaca ttcttgtttt aagtgccttt 3720agttttaaca gttcactttt tacagtgcta tttactgaag ttatttatta aatatgccta 3780aaatacttaa atcggatgtc ttgactctga tgtattttat caggttgtgt gcatgaaatt 3840tttatagatt aaagaagttg aggaaaagca aaaaaaaaa 3879353392DNAHomo sapiens 35gcggagccag cccctcccct acccggagca gcccgctggg gccgtcccga gcggcgacac 60actaggagtc ccggccggcc agccagggca gccgcggtcc cgggactcgg ccgtgagtgc 120tgcgggacgg atggtggcgg cggggcgcgg gccagcgcgg gcgccgtgag ccggagctgc 180gcgcggggca tgcggctgcg gcccccggcc ctcggccccc gcgctccggc cccagccccg 240gccgccggcc cccgcggagt gcagcgaccg cgccgccgct gagggaggcg ccccaccatg 300ccgcgggccc cggcgccgct gtacgcctgc ctcctggggc tctgcgcgct cctgccccgg 360ctcgcaggtc tcaacatatg cactagtgga agtgccacct catgtgaaga atgtctgcta 420atccacccaa aatgtgcctg gtgctccaaa gaggacttcg gaagcccacg gtccatcacc 480tctcggtgtg atctgagggc aaaccttgtc aaaaatggct gtggaggtga gatagagagc 540ccagccagca gcttccatgt cctgaggagc ctgcccctca gcagcaaggg ttcgggctct 600gcaggctggg acgtcattca gatgacacca caggagattg ccgtgaacct ccggcccggt 660gacaagacca ccttccagct acaggttcgc caggtggagg actatcctgt ggacctgtac 720tacctgatgg acctctccct gtccatgaag gatgacttgg acaatatccg gagcctgggc 780accaaactcg cggaggagat gaggaagctc accagcaact tccggttggg atttgggtct 840tttgttgata aggacatctc tcctttctcc tacacggcac cgaggtacca gaccaatccg 900tgcattggtt acaagttgtt tccaaattgc gtcccctcct ttgggttccg ccatctgctg 960cctctcacag acagagtgga cagcttcaat gaggaagttc ggaaacagag ggtgtcccgg 1020aaccgagatg cccctgaggg gggctttgat gcagtactcc aggcagccgt ctgcaaggag 1080aagattggct ggcgaaagga tgcactgcat ttgctggtgt tcacaacaga tgatgtgccc 1140cacatcgcat tggatggaaa attgggaggc ctggtgcagc cacacgatgg ccagtgccac 1200ctgaacgagg ccaacgagta cactgcatcc aaccagatgg actatccatc ccttgccttg 1260cttggagaga aattggcaga gaacaacatc aacctcatct ttgcagtgac aaaaaaccat 1320tatatgctgt acaagaattt tacagccctg atacctggaa caacggtgga gattttagat 1380ggagactcca aaaatattat

tcaactgatt attaatgcat acaatagtat ccggtctaaa 1440gtggagttgt cagtctggga tcagcctgag gatcttaatc tcttctttac tgctacctgc 1500caagatgggg tatcctatcc tggtcagagg aagtgtgagg gtctgaagat tggggacacg 1560gcatcttttg aagtatcatt ggaggcccga agctgtccca gcagacacac ggagcatgtg 1620tttgccctgc ggccggtggg attccgggac agcctggagg tgggggtcac ctacaactgc 1680acgtgcggct gcagcgtggg gctggaaccc aacagtgcca ggtgcaacgg gagcgggacc 1740tatgtctgcg gcctgtgtga gtgcagcccc ggctacctgg gcaccaggtg cgagtgccag 1800gatggggaga accagagcgt gtaccagaac ctgtgccggg aggcagaggg caagccactg 1860tgcagcgggc gtggggactg cagctgcaac cagtgctcct gcttcgagag cgagttcggc 1920aagatctatg ggcctttctg tgagtgcgac aacttctcct gtgccaggaa caagggagtc 1980ctctgctcag gccatggcga gtgtcactgc ggggaatgca agtgccatgc aggttacatc 2040ggggacaact gtaactgctc gacagacatc agcacatgcc ggggcagaga tggccagatc 2100tgcagcgagc gtgggcactg tctctgtggg cagtgccaat gcacggagcc gggggccttt 2160ggggagatgt gtgagaagtg ccccacctgc ccggatgcat gcagcaccaa gagagattgc 2220gtcgagtgcc tgctgctcca ctctgggaaa cctgacaacc agacctgcca cagcctatgc 2280agggatgagg tgatcacatg ggtggacacc atcgtgaaag atgaccagga ggctgtgcta 2340tgtttctaca aaaccgccaa ggactgcgtc atgatgttca cctatgtgga gctccccagt 2400gggaagtcca acctgaccgt cctcagggag ccagagtgtg gaaacacccc caacgccatg 2460accatcctcc tggctgtggt cggtagcatc ctccttgttg ggcttgcact cctggctatc 2520tggaagctgc ttgtcaccat ccacgaccgg agggagtttg caaagtttca gagcgagcga 2580tccagggccc gctatgaaat ggcttcaaat ccattataca gaaagcctat ctccacgcac 2640actgtggact tcaccttcaa caagttcaac aaatcctaca atggcactgt ggactgatgt 2700ttccttctcc gaggggctgg agcggggatc tgatgaaaag gtcagactga aacgccttgc 2760acggctgctc ggcttgatca cagctcccta ggtaggcacc acagagaaga ccttctagtg 2820agcctgggcc aggagcccac agtgcctgta caggaaggtg cctggccatg tcacctggct 2880gctaggccag agccatgcca ggctgcgtcc ctccgagctt gggataaagc aaggggacct 2940tggcactctc agctttccct gccacatcca gcttgttgtc ccaatgaaat actgagatgc 3000tgggctgtct ctcccttcca ggaatgctgg gcccccagcc tggccagaca agacgactgt 3060caggaagggt cggagtctgt aaaaccagca tacagtttgg cttttttcac attgatcatt 3120tttatatgaa ataaaaagat cctgcattta tggtgtagtt ctgagtcctg agacttttcc 3180gcgtgatggc tatgccttgc acacaggtgt tggtgatggg gctgttgaga tgcctgttga 3240aggtacatcg tttgcaaatg tcagtttcct ctcctgtccg tgtttgttta gtacttttat 3300aatgaaaaga aacaagattg tttgggattg gaagtaaaga ttaaaaccaa aagaatttgt 3360gtttgtctga taaaaaaaaa aaaaaaaaaa aa 3392363338DNAHomo sapiens 36gacatcatgg gctattttta ggggttgact ggtagcagat aagtgttgag ctcgggctgg 60ataagggctc agagttgcac tgagtgtggc tgaagcagcg aggcgggagt ggaggtgcgc 120ggagtcaggc agacagacag acacagccag ccagccaggt cggcagtata gtccgaactg 180caaatcttat tttcttttca ccttctctct aactgcccag agctagcgcc tgtggctccc 240gggctggtgt ttcgggagtg tccagagagc ctggtctcca gccgcccccg ggaggagagc 300cctgctgccc aggcgctgtt gacagcggcg gaaagcagcg gtacccacgc gcccgccggg 360ggaagtcggc gagcggctgc agcagcaaag aactttcccg gctgggagga ccggagacaa 420gtggcagagt cccggagcga acttttgcaa gcctttcctg cgtcttaggc ttctccacgg 480cggtaaagac cagaaggcgg cggagagcca cgcaagagaa gaaggacgtg cgctcagctt 540cgctcgcacc ggttgttgaa cttgggcgag cgcgagccgc ggctgccggg cgccccctcc 600ccctagcagc ggaggagggg acaagtcgtc ggagtccggg cggccaagac ccgccgccgg 660ccggccactg cagggtccgc actgatccgc tccgcgggga gagccgctgc tctgggaagt 720gagttcgcct gcggactccg aggaaccgct gcgcccgaag agcgctcagt gagtgaccgc 780gacttttcaa agccgggtag cgcgcgcgag tcgacaagta agagtgcggg aggcatctta 840attaaccctg cgctccctgg agcgagctgg tgaggagggc gcagcgggga cgacagccag 900cgggtgcgtg cgctcttaga gaaactttcc ctgtcaaagg ctccgggggg cgcgggtgtc 960ccccgcttgc cagagccctg ttgcggcccc gaaacttgtg cgcgcagccc aaactaacct 1020cacgtgaagt gacggactgt tctatgactg caaagatgga aacgaccttc tatgacgatg 1080ccctcaacgc ctcgttcctc ccgtccgaga gcggacctta tggctacagt aaccccaaga 1140tcctgaaaca gagcatgacc ctgaacctgg ccgacccagt ggggagcctg aagccgcacc 1200tccgcgccaa gaactcggac ctcctcacct cgcccgacgt ggggctgctc aagctggcgt 1260cgcccgagct ggagcgcctg ataatccagt ccagcaacgg gcacatcacc accacgccga 1320cccccaccca gttcctgtgc cccaagaacg tgacagatga gcaggagggc ttcgccgagg 1380gcttcgtgcg cgccctggcc gaactgcaca gccagaacac gctgcccagc gtcacgtcgg 1440cggcgcagcc ggtcaacggg gcaggcatgg tggctcccgc ggtagcctcg gtggcagggg 1500gcagcggcag cggcggcttc agcgccagcc tgcacagcga gccgccggtc tacgcaaacc 1560tcagcaactt caacccaggc gcgctgagca gcggcggcgg ggcgccctcc tacggcgcgg 1620ccggcctggc ctttcccgcg caaccccagc agcagcagca gccgccgcac cacctgcccc 1680agcagatgcc cgtgcagcac ccgcggctgc aggccctgaa ggaggagcct cagacagtgc 1740ccgagatgcc cggcgagaca ccgcccctgt cccccatcga catggagtcc caggagcgga 1800tcaaggcgga gaggaagcgc atgaggaacc gcatcgctgc ctccaagtgc cgaaaaagga 1860agctggagag aatcgcccgg ctggaggaaa aagtgaaaac cttgaaagct cagaactcgg 1920agctggcgtc cacggccaac atgctcaggg aacaggtggc acagcttaaa cagaaagtca 1980tgaaccacgt taacagtggg tgccaactca tgctaacgca gcagttgcaa acattttgaa 2040gagagaccgt cgggggctga ggggcaacga agaaaaaaaa taacacagag agacagactt 2100gagaacttga caagttgcga cggagagaaa aaagaagtgt ccgagaacta aagccaaggg 2160tatccaagtt ggactgggtt gcgtcctgac ggcgccccca gtgtgcacga gtgggaagga 2220cttggcgcgc cctcccttgg cgtggagcca gggagcggcc gcctgcgggc tgccccgctt 2280tgcggacggg ctgtccccgc gcgaacggaa cgttggactt ttcgttaaca ttgaccaaga 2340actgcatgga cctaacattc gatctcattc agtattaaag gggggagggg gagggggtta 2400caaactgcaa tagagactgt agattgcttc tgtagtactc cttaagaaca caaagcgggg 2460ggagggttgg ggaggggcgg caggagggag gtttgtgaga gcgaggctga gcctacagat 2520gaactctttc tggcctgcct tcgttaactg tgtatgtaca tatatatatt ttttaatttg 2580atgaaagctg attactgtca ataaacagct tcatgccttt gtaagttatt tcttgtttgt 2640ttgtttgggt atcctgccca gtgttgtttg taaataagag atttggagca ctctgagttt 2700accatttgta ataaagtata taattttttt atgttttgtt tctgaaaatt ccagaaagga 2760tatttaagaa aatacaataa actattggaa agtactcccc taacctcttt tctgcatcat 2820ctgtagatac tagctatcta ggtggagttg aaagagttaa gaatgtcgat taaaatcact 2880ctcagtgctt cttactatta agcagtaaaa actgttctct attagacttt agaaataaat 2940gtacctgatg tacctgatgc tatggtcagg ttatactcct cctcccccag ctatctatat 3000ggaattgctt accaaaggat agtgcgatgt ttcaggaggc tggaggaagg ggggttgcag 3060tggagaggga cagcccactg agaagtcaaa catttcaaag tttggattgt atcaagtggc 3120atgtgctgtg accatttata atgttagtag aaattttaca ataggtgctt attctcaaag 3180caggaattgg tggcagattt tacaaaagat gtatccttcc aatttggaat cttctctttg 3240acaattccta gataaaaaga tggcctttgc ttatgaatat ttataacagc attcttgtca 3300caataaatgt attcaaatac caaaaaaaaa aaaaaaaa 3338371832DNAHomo sapiens 37gagcggccag gccagcctcg gagccagcag ggagctggga gctgggggaa acgacgccag 60gaaagctatc gcgccagaga gggcgacggg ggctcgggaa gcctgacagg gcttttgcgc 120acagctgccg gctggctgct acccgcccgc gccagccccc gagaacgcgc gaccaggcac 180ccagtccggt caccgcagcg gagagctcgc cgctcgctgc agcgaggccc ggagcggccc 240cgcagggacc ctccccagac cgcctgggcc gcccggatgt gcactaaaat ggaacagccc 300ttctaccacg acgactcata cacagctacg ggatacggcc gggcccctgg tggcctctct 360ctacacgact acaaactcct gaaaccgagc ctggcggtca acctggccga cccctaccgg 420agtctcaaag cgcctggggc tcgcggaccc ggcccagagg gcggcggtgg cggcagctac 480ttttctggtc agggctcgga caccggcgcg tctctcaagc tcgcctcttc ggagctggaa 540cgcctgattg tccccaacag caacggcgtg atcacgacga cgcctacacc cccgggacag 600tacttttacc cccgcggggg tggcagcggt ggaggtgcag ggggcgcagg gggcggcgtc 660accgaggagc aggagggctt cgccgacggc tttgtcaaag ccctggacga tctgcacaag 720atgaaccacg tgacaccccc caacgtgtcc ctgggcgcta ccggggggcc cccggctggg 780cccgggggcg tctacgccgg cccggagcca cctcccgttt acaccaacct cagcagctac 840tccccagcct ctgcgtcctc gggaggcgcc ggggctgccg tcgggaccgg gagctcgtac 900ccgacgacca ccatcagcta cctcccacac gcgccgccct tcgccggtgg ccacccggcg 960cagctgggct tgggccgcgg cgcctccacc ttcaaggagg aaccgcagac cgtgccggag 1020gcgcgcagcc gggacgccac gccgccggtg tcccccatca acatggaaga ccaagagcgc 1080atcaaagtgg agcgcaagcg gctgcggaac cggctggcgg ccaccaagtg ccggaagcgg 1140aagctggagc gcatcgcgcg cctggaggac aaggtgaaga cgctcaaggc cgagaacgcg 1200gggctgtcga gtaccgccgg cctcctccgg gagcaggtgg cccagctcaa acagaaggtc 1260atgacccacg tcagcaacgg ctgtcagctg ctgcttgggg tcaagggaca cgccttctga 1320acgtcccctg cccctttacg gacaccccct cgcttggacg gctgggcaca cgcctcccac 1380tggggtccag ggagcaggcg gtgggcaccc accctgggac ctaggggcgc cgcaaaccac 1440actggactcc ggccctccta ccctgcgccc agtccttcca cctcgacgtt tacaagcccc 1500cccttccact tttttttgta tgtttttttt ctgctggaaa cagactcgat tcatattgaa 1560tataatatat ttgtgtattt aacagggagg ggaagagggg gcgatcgcgg cggagctggc 1620cccgccgcct ggtactcaag cccgcgggga cattgggaag gggacccccg ccccctgccc 1680tcccctctct gcaccgtact gtggaaaaga aacacgcact tagtctctaa agagtttatt 1740ttaagacgtg tttgtgtttg tgtgtgtttg ttctttttat tgaatctatt taagtaaaaa 1800aaaaattggt tctttaaaaa aaaaaaaaaa aa 1832382187DNAHomo sapiens 38gtcctttcta gacagccccc tcctccaggc tcagggacct gtctggctgt gagctcccag 60gaggtcccag gggtgtgacc tccctccctc cctccctccc tcttcccttc accccaggcc 120agcccagggc cagctataaa gctggcccag cctggctctc agcacaccca gctgcctgag 180accctccttc aacctcccta gaggacagcc ccactctgcc tcctgctccc ccagggcagc 240accatgtggc ccctgtggct ctgctgggca ctctgggtgc tgcccctggc tggccccggg 300gcggccctga ccgaggagca gctcctgggc agcctgctgc ggcagctgca gctcagcgag 360gtgcccgtac tggacagggc cgacatggag aagctggtca tccccgccca cgtgagggcc 420cagtatgtag tcctgctgcg gcgcagccac ggggaccgct cccgcggaaa gaggttcagc 480cagagcttcc gagaggtggc cggcaggttc ctggcgtcgg aggccagcac acacctgctg 540gtgttcggca tggagcagcg gctgccgccc aacagcgagc tggtgcaggc cgtgctgcgg 600ctcttccagg agccggtccc caaggccgcg ctgcacaggc acgggcggct gtccccgcgc 660agcgcccagg cccgggtgac cgtcgagtgg ctgcgcgtcc gcgacgacgg ctccaaccgc 720acctccctca tcgactccag gctggtgtcc gtccacgaga gcggctggaa ggccttcgac 780gtgaccgagg ccgtgaactt ctggcagcag ctgagccggc cccggcagcc gctgctgcta 840caggtgtcgg tgcagaggga gcatctgggc ccgctggcgt ccggcgccca caagctggtc 900cgctttgcct cgcagggggc gccagccggg cttggggagc cccagctgga gctgcacacc 960ctggacctca gggactatgg agctcagggc gactgtgacc ctgaagcacc aatgaccgag 1020ggcacccgct gctgccgcca ggagatgtac attgacctgc aggggatgaa gtgggccaag 1080aactgggtgc tggagccccc gggcttcctg gcttacgagt gtgtgggcac ctgccagcag 1140cccccggagg ccctggcctt caattggcca tttctggggc cgcgacagtg tatcgcctcg 1200gagactgcct cgctgcccat gatcgtcagc atcaaggagg gaggcaggac caggccccag 1260gtggtcagcc tgcccaacat gagggtgcag aagtgcagct gtgcctcgga tggggcgctc 1320gtgccaagga ggctccagcc ataggcgcct ggtgtatcca ttgagccctc taactgaacg 1380tgtgcataga ggtggtctta atgtaggtct taactttata cttagcaagt tactccatcc 1440caatttagtg ctcctgtgtg accttcgccc tgtgtccttc catttcctgt ctttcccgtc 1500catcacccat cctaagcact tacgtgagta aataatgcag ctcagatgct gagctctagt 1560aggaaatgct ggcatgctga ttacaagata cagctgagca atgcacacat tttcagctgg 1620gagtttctgt tctctggcaa attcttcact gagtctggaa caataatacc ctatgattag 1680aactggggaa acagaactga attgctgtgt tatatgagga attaaaacct tcaaatctct 1740atttccccca aatactgacc cattctggac ttttgtaaac atacctaggc ccctgttccc 1800ctgagagggt gctaagagga aggatgaagg gcttcaggct gggggcagtg gacagggaat 1860tgggatacct ggattctggt tctgacaggg ccacaagcta ggatctctaa caaacgcaga 1920aggctttggc tcgtcatttc ctcttaaaaa ggaggagctg ggcttcagct ctaagaactt 1980cattgccctg gggatcagac agcccctacc tacccctgcc cactcctctg gagactgagc 2040cttgcccgtg catatttagg tcatttccca cactgtctta gagaacttgt caccagaaac 2100cacatgtatt tgcatgtttt ttgttaattt agctaaagca attgaatgta gatactcaga 2160agaaataaaa aatgatgttt cactctg 2187392048DNAHomo sapiens 39cctggcccgg gagggtataa gtgcggcccg cgcccctccg agcggcgcgc tgggttccgg 60agcgatggcc acagccgagt cccgtgcgct ccagtttgcc gagggcgccg cgtttccagc 120gtaccgggcc ccccacgccg gcggggcgct cctgccgccc ccgagccctg cggcagccct 180gctccctgcg ccgcccgcgg gccccggccc agcgaccttt gcgggcttcc tcggccggga 240ccccgggccg gccccgccgc cccccgccag cctgggctcg cctgcgcccc ccaaaggcgc 300ggccgccccg tcggcgtcgc agcgccgcaa gcgcacgtct ttcagcgccg aacagctgca 360gctgctggag ctcgtcttcc gccggacccg gtaccccgac atccacttgc gcgagcgcct 420ggccgcgctc accctgctcc ccgagtccag gatccagctt ttattttctc ccctcttcca 480ggtatggttc cagaacaggc gtgccaagtc tcggcgtcag agtgggaaat ccttccaacc 540tttggctagg ccggagatta tcctcaacca ctgtgctcct ggaactgaaa cgaaatgtct 600gaagccccag ctgcctcttg aggtagatgt gaactgcctg cccgaaccaa acggggttgg 660agggggcatc tctgactcta gctcccaagg tcagaatttt gaaacctgtt cccctctctc 720tgaagacatt ggttcaaagc tggactcatg ggaggaacac atcttttctg cctttggtaa 780cttttgagga ttctgggaga attcgggata agctctgagg agccatgact gacagcctgg 840gagagacaca tcagcatact gtcctttctg acttccatgc taaggacatg tccttgttaa 900ccttgatgat ggttttgaca gcacctctca catttgaagg taccccgcca ctttgtcaat 960gacgttttaa gcccacactc ccaccccaga gttcccgcat tcgtttttac ctgtgttctc 1020tccaagcctg cacattccat tggtctgcat ccctatgcct tcttgccagg cctgttttta 1080gtttttggac tggttgttca gaactcatta ttttcttcac aagaatgcct cagcttgact 1140cagtttcccc ttgtgtttga cagctgccat tttctcctgg tccctccaag gcttataatc 1200ttaaagtcac tctaccccgt ctcttcaacc ctcatcctag gtttattact ttttaaaatt 1260gggcctgtca tcttcacgtt caatcatagc tccaatgact ctgcatgcag attatttcga 1320cagccccctt gcctctagct tctcaactac ttaaaaaaaa ttaccctctg tgggccaggt 1380gcagtggctc actcctgcaa tctcagcact ttgggaggcc gagtgggtgg atcacctgaa 1440gtcaggagtt caagaccagc ctggccaata tggcgaaacc ccatctctgc taaaaatata 1500aaacttagct gggcacggtg acgggagcct gtagtcccag ctactcagga ggctgaggca 1560ggagaatcac ttgagcctgg gaggtggagg ttgcagtgat ctaagatcgt gccactgcac 1620ttcagcctgg gagacagagg gaggctctca aaaaaaaaaa aaaaaaaaaa aaaaattact 1680ctatggttct gtggtagcct ccagttgcta ccaaattata aaaagctttc agttaccctc 1740ccagataact gatatcatcc ttagcctgca ggacagctat gcaaatctga aggtcaacta 1800tccacaatat atgctttggt cttaaagtca ctcctttcag ttttgaacca aattcatacc 1860ttttgctttc aaaacactcg aggactcccc acctgccttc tgaagtctga aattttctct 1920aagtaatcct gattttgcac ctgttacttc gatcactcca ttacccttag cacttgttat 1980tgtacttcct gtgcaagttt tgtggattat taaatgtctt tcacaaatgt aaaaaaaaaa 2040aaaaaaaa 2048402735DNAHomo sapiens 40acaacagtcc ccaggcatca ccattcaaga tgcatccagg ggtcctggct gccttcctct 60tcttgagctg gactcattgt cgggccctgc cccttcccag tggtggtgat gaagatgatt 120tgtctgagga agacctccag tttgcagagc gctacctgag atcatactac catcctacaa 180atctcgcggg aatcctgaag gagaatgcag caagctccat gactgagagg ctccgagaaa 240tgcagtcttt cttcggctta gaggtgactg gcaaacttga cgataacacc ttagatgtca 300tgaaaaagcc aagatgcggg gttcctgatg tgggtgaata caatgttttc cctcgaactc 360ttaaatggtc caaaatgaat ttaacctaca gaattgtgaa ttacacccct gatatgactc 420attctgaagt cgaaaaggca ttcaaaaaag ccttcaaagt ttggtccgat gtaactcctc 480tgaattttac cagacttcac gatggcattg ctgacatcat gatctctttt ggaattaagg 540agcatggcga cttctaccca tttgatgggc cctctggcct gctggctcat gcttttcctc 600ctgggccaaa ttatggagga gatgcccatt ttgatgatga tgaaacctgg acaagtagtt 660ccaaaggcta caacttgttt cttgttgctg cgcatgagtt cggccactcc ttaggtcttg 720accactccaa ggaccctgga gcactcatgt ttcctatcta cacctacacc ggcaaaagcc 780actttatgct tcctgatgac gatgtacaag ggatccagtc tctctatggt ccaggagatg 840aagaccccaa ccctaaacat ccaaaaacgc cagacaaatg tgacccttcc ttatcccttg 900atgccattac cagtctccga ggagaaacaa tgatctttaa agacagattc ttctggcgcc 960tgcatcctca gcaggttgat gcggagctgt ttttaacgaa atcattttgg ccagaacttc 1020ccaaccgtat tgatgctgca tatgagcacc cttctcatga cctcatcttc atcttcagag 1080gtagaaaatt ttgggctctt aatggttatg acattctgga aggttatccc aaaaaaatat 1140ctgaactggg tcttccaaaa gaagttaaga agataagtgc agctgttcac tttgaggata 1200caggcaagac tctcctgttc tcaggaaacc aggtctggag atatgatgat actaaccata 1260ttatggataa agactatccg agactaatag aagaagactt cccaggaatt ggtgataaag 1320tagatgctgt ctatgagaaa aatggttata tctatttttt caacggaccc atacagtttg 1380aatacagcat ctggagtaac cgtattgttc gcgtcatgcc agcaaattcc attttgtggt 1440gttaagtgtc tttttaaaaa ttgttattta aatcctgaag agcatttggg gtaatacttc 1500cagaagtgcg gggtagggga agaagagcta tcaggagaaa gcttggttct gtgaacaagc 1560ttcagtaagt tatctttgaa tatgtagtat ctatatgact atgcgtggct ggaaccacat 1620tgaagaatgt tagagtaatg aaatggagga tctctaaaga gcatctgatt cttgttgctg 1680tacaaaagca atggttgatg atacttccca caccacaaat gggacacatg gtctgtcaat 1740gagagcataa tttaaaaata tatttataag gaaattttac aagggcataa agtaaataca 1800tgcatataat gaataaatca ttcttactaa aaagtataaa atagtatgaa aatggaaatt 1860tgggagagcc atacataaaa gaaataaacc aaaggaaaat gtctgtaata atagactgta 1920acttccaaat aaataatttt cattttgcac tgaggatatt cagatgtatg tgcccttctt 1980cacacagaca ctaacgaaat atcaaagtca ttaaagacag gagacaaaag agcagtggta 2040agaatagtag atgtggcctt tgaattctgt ttaattttca cttttggcaa tgactcaaag 2100tctgctctca tataagacaa atattccttt gcatattata aaggataaag aaggatgatg 2160tctttttatt aaaatatttc aggttcttca gaagtcacac attacaaagt taaaattgtt 2220atcaaaatag tctaaggcca tggcatccct ttttcataaa ttatttgatt atttaagact 2280aaaagttgca ttttaaccct attttaccta gctaattatt taattgtcca gtttgtcttg 2340gatatatagg ctattttcta aagacttgta tagcatgaaa taaaatatat cttataaagt 2400ggaagtatgt atattaaaaa agagacatcc aaattttttt ttaaagcagt ctactagatt 2460gtgatccctt gagatatgga aggatgcctt tttttctctg catttaaaaa aatcccccag 2520cacttcccac agtgcctatt gatacttggg gagggtgctt ggcacttatt gaatatatga 2580tcggccatca agggaagaac tattgtgctc agagacactg ttgataaaaa ctcaggcaaa 2640gaaaatgaaa tgcatatttg caaagtgtat taggaagtgt ttatgttgtt tataataaaa 2700atatattttc aacagacaaa aaaaaaaaaa aaaaa 2735413549DNAHomo sapiens 41acatctggcg gctgccctcc cttgtttccg ctgcatccag acttcctcag gcggtggctg 60gaggctgcgc atctggggct ttaaacatac aaagggattg ccaggacctg cggcggcggc 120ggcggcggcg ggggctgggg cgcgggggcc ggaccatgag ccgctgagcc gggcaaaccc 180caggccaccg agccagcgga ccctcggagc gcagccctgc gccgcggagc aggctccaac 240caggcggcga ggcggccaca cgcaccgagc cagcgacccc cgggcgacgc gcggggccag 300ggagcgctac gatggaggcg ctaatggccc ggggcgcgct cacgggtccc ctgagggcgc 360tctgtctcct gggctgcctg ctgagccacg ccgccgccgc gccgtcgccc atcatcaagt 420tccccggcga tgtcgccccc aaaacggaca aagagttggc agtgcaatac ctgaacacct 480tctatggctg ccccaaggag agctgcaacc tgtttgtgct gaaggacaca ctaaagaaga 540tgcagaagtt ctttggactg ccccagacag gtgatcttga ccagaatacc atcgagacca 600tgcggaagcc acgctgcggc

aacccagatg tggccaacta caacttcttc cctcgcaagc 660ccaagtggga caagaaccag atcacataca ggatcattgg ctacacacct gatctggacc 720cagagacagt ggatgatgcc tttgctcgtg ccttccaagt ctggagcgat gtgaccccac 780tgcggttttc tcgaatccat gatggagagg cagacatcat gatcaacttt ggccgctggg 840agcatggcga tggatacccc tttgacggta aggacggact cctggctcat gccttcgccc 900caggcactgg tgttggggga gactcccatt ttgatgacga tgagctatgg accttgggag 960aaggccaagt ggtccgtgtg aagtatggga acgccgatgg ggagtactgc aagttcccct 1020tcttgttcaa tggcaaggag tacaacagct gcactgatac cggccgcagc gatggcttcc 1080tctggtgctc caccacctac aactttgaga aggatggcaa gtacggcttc tgtccccatg 1140aagccctgtt caccatgggc ggcaacgctg aaggacagcc ctgcaagttt ccattccgct 1200tccagggcac atcctatgac agctgcacca ctgagggccg cacggatggc taccgctggt 1260gcggcaccac tgaggactac gaccgcgaca agaagtatgg cttctgccct gagaccgcca 1320tgtccactgt tggtgggaac tcagaaggtg ccccctgtgt cttccccttc actttcctgg 1380gcaacaaata tgagagctgc accagcgccg gccgcagtga cggaaagatg tggtgtgcga 1440ccacagccaa ctacgatgat gaccgcaagt ggggcttctg ccctgaccaa gggtacagcc 1500tgttcctcgt ggcagcccac gagtttggcc acgccatggg gctggagcac tcccaagacc 1560ctggggccct gatggcaccc atttacacct acaccaagaa cttccgtctg tcccaggatg 1620acatcaaggg cattcaggag ctctatgggg cctctcctga cattgacctt ggcaccggcc 1680ccacccccac gctgggccct gtcactcctg agatctgcaa acaggacatt gtatttgatg 1740gcatcgctca gatccgtggt gagatcttct tcttcaagga ccggttcatt tggcggactg 1800tgacgccacg tgacaagccc atggggcccc tgctggtggc cacattctgg cctgagctcc 1860cggaaaagat tgatgcggta tacgaggccc cacaggagga gaaggctgtg ttctttgcag 1920ggaatgaata ctggatctac tcagccagca ccctggagcg agggtacccc aagccactga 1980ccagcctggg actgccccct gatgtccagc gagtggatgc cgcctttaac tggagcaaaa 2040acaagaagac atacatcttt gctggagaca aattctggag atacaatgag gtgaagaaga 2100aaatggatcc tggcttcccc aagctcatcg cagatgcctg gaatgccatc cccgataacc 2160tggatgccgt cgtggacctg cagggcggcg gtcacagcta cttcttcaag ggtgcctatt 2220acctgaagct ggagaaccaa agtctgaaga gcgtgaagtt tggaagcatc aaatccgact 2280ggctaggctg ctgagctggc cctggctccc acaggccctt cctctccact gccttcgata 2340caccgggcct ggagaactag agaaggaccc ggaggggcct ggcagccgtg ccttcagctc 2400tacagctaat cagcattctc actcctacct ggtaatttaa gattccagag agtggctcct 2460cccggtgccc aagaatagat gctgactgta ctcctcccag gcgccccttc cccctccaat 2520cccaccaacc ctcagagcca cccctaaaga gatactttga tattttcaac gcagccctgc 2580tttgggctgc cctggtgctg ccacacttca ggctcttctc ctttcacaac cttctgtggc 2640tcacagaacc cttggagcca atggagactg tctcaagagg gcactggtgg cccgacagcc 2700tggcacaggg cagtgggaca gggcatggcc aggtggccac tccagacccc tggcttttca 2760ctgctggctg ccttagaacc tttcttacat tagcagtttg ctttgtatgc actttgtttt 2820tttctttggg tcttgttttt tttttccact tagaaattgc atttcctgac agaaggactc 2880aggttgtctg aagtcactgc acagtgcatc tcagcccaca tagtgatggt tcccctgttc 2940actctactta gcatgtccct accgagtctc ttctccactg gatggaggaa aaccaagccg 3000tggcttcccg ctcagccctc cctgcccctc ccttcaacca ttccccatgg gaaatgtcaa 3060caagtatgaa taaagacacc tactgagtgg ccgtgtttgc catctgtttt agcagagcct 3120agacaagggc cacagaccca gccagaagcg gaaacttaaa aagtccgaat ctctgctccc 3180tgcagggcac aggtgatggt gtctgctgga aaggtcagag cttccaaagt aaacagcaag 3240agaacctcag ggagagtaag ctctagtccc tctgtcctgt agaaagagcc ctgaagaatc 3300agcaattttg ttgctttatt gtggcatctg ttcgaggttt gcttcctctt taagtctgtt 3360tcttcattag caatcatatc agttttaatg ctactactaa caatgaacag taacaataat 3420atccccctca attaatagag tgctttctat gtgcaaggca cttttcacgt gtcacctatt 3480ttaacctttc caaccacata aataaaaaag gccattatta gttgaaaaaa aaaaaaaaaa 3540aaaaaaaaa 3549422387DNAHomo sapiens 42agacacctct gccctcacca tgagcctctg gcagcccctg gtcctggtgc tcctggtgct 60gggctgctgc tttgctgccc ccagacagcg ccagtccacc cttgtgctct tccctggaga 120cctgagaacc aatctcaccg acaggcagct ggcagaggaa tacctgtacc gctatggtta 180cactcgggtg gcagagatgc gtggagagtc gaaatctctg gggcctgcgc tgctgcttct 240ccagaagcaa ctgtccctgc ccgagaccgg tgagctggat agcgccacgc tgaaggccat 300gcgaacccca cggtgcgggg tcccagacct gggcagattc caaacctttg agggcgacct 360caagtggcac caccacaaca tcacctattg gatccaaaac tactcggaag acttgccgcg 420ggcggtgatt gacgacgcct ttgcccgcgc cttcgcactg tggagcgcgg tgacgccgct 480caccttcact cgcgtgtaca gccgggacgc agacatcgtc atccagtttg gtgtcgcgga 540gcacggagac gggtatccct tcgacgggaa ggacgggctc ctggcacacg cctttcctcc 600tggccccggc attcagggag acgcccattt cgacgatgac gagttgtggt ccctgggcaa 660gggcgtcgtg gttccaactc ggtttggaaa cgcagatggc gcggcctgcc acttcccctt 720catcttcgag ggccgctcct actctgcctg caccaccgac ggtcgctccg acggcttgcc 780ctggtgcagt accacggcca actacgacac cgacgaccgg tttggcttct gccccagcga 840gagactctac acccaggacg gcaatgctga tgggaaaccc tgccagtttc cattcatctt 900ccaaggccaa tcctactccg cctgcaccac ggacggtcgc tccgacggct accgctggtg 960cgccaccacc gccaactacg accgggacaa gctcttcggc ttctgcccga cccgagctga 1020ctcgacggtg atggggggca actcggcggg ggagctgtgc gtcttcccct tcactttcct 1080gggtaaggag tactcgacct gtaccagcga gggccgcgga gatgggcgcc tctggtgcgc 1140taccacctcg aactttgaca gcgacaagaa gtggggcttc tgcccggacc aaggatacag 1200tttgttcctc gtggcggcgc atgagttcgg ccacgcgctg ggcttagatc attcctcagt 1260gccggaggcg ctcatgtacc ctatgtaccg cttcactgag gggcccccct tgcataagga 1320cgacgtgaat ggcatccggc acctctatgg tcctcgccct gaacctgagc cacggcctcc 1380aaccaccacc acaccgcagc ccacggctcc cccgacggtc tgccccaccg gaccccccac 1440tgtccacccc tcagagcgcc ccacagctgg ccccacaggt cccccctcag ctggccccac 1500aggtcccccc actgctggcc cttctacggc cactactgtg cctttgagtc cggtggacga 1560tgcctgcaac gtgaacatct tcgacgccat cgcggagatt gggaaccagc tgtatttgtt 1620caaggatggg aagtactggc gattctctga gggcaggggg agccggccgc agggcccctt 1680ccttatcgcc gacaagtggc ccgcgctgcc ccgcaagctg gactcggtct ttgaggagcg 1740gctctccaag aagcttttct tcttctctgg gcgccaggtg tgggtgtaca caggcgcgtc 1800ggtgctgggc ccgaggcgtc tggacaagct gggcctggga gccgacgtgg cccaggtgac 1860cggggccctc cggagtggca gggggaagat gctgctgttc agcgggcggc gcctctggag 1920gttcgacgtg aaggcgcaga tggtggatcc ccggagcgcc agcgaggtgg accggatgtt 1980ccccggggtg cctttggaca cgcacgacgt cttccagtac cgagagaaag cctatttctg 2040ccaggaccgc ttctactggc gcgtgagttc ccggagtgag ttgaaccagg tggaccaagt 2100gggctacgtg acctatgaca tcctgcagtg ccctgaggac tagggctccc gtcctgcttt 2160ggcagtgcca tgtaaatccc cactgggacc aaccctgggg aaggagccag tttgccggat 2220acaaactggt attctgttct ggaggaaagg gaggagtgga ggtgggctgg gccctctctt 2280ctcacctttg ttttttgttg gagtgtttct aataaacttg gattctctaa cctttaaaaa 2340aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaa 2387432224DNAHomo sapiens 43tcccgtctcc gcagcaaaaa agtttgagtc gccgctgccg ggttgccagc ggagtcgcgc 60gtcgggagct acgtagggca gagaagtcat ggcttctccg tccaaaggca atgacttgtt 120ttcgcccgac gaggagggcc cagcagtggt ggccggacca ggcccggggc ctgggggcgc 180cgagggggcc gcggaggagc gccgcgtcaa ggtctccagc ctgcccttca gcgtggaggc 240gctcatgtcc gacaagaagc cgcccaagga ggcgtccccg ctgccggccg aaagcgcctc 300ggccggggcc accctgcggc cactgctgct gtcggggcac ggcgctcggg aagcgcacag 360ccccgggccg ctggtgaagc ccttcgagac cgcctcggtc aagtcggaaa attcagaaga 420tggagcggcg tggatgcagg aacccggccg atattcgccg ccgccaagac atatgagccc 480taccacctgc accctgagga aacacaagac caatcggaag ccgcgcacgc cctttaccac 540atcccagctc ctcgccctgg agcgcaagtt ccgtcagaaa cagtacctct ccattgcaga 600gcgtgcagag ttctccagct ctctgaacct cacagagacc caggtcaaaa tctggttcca 660gaaccgaagg gccaaggcga aaagactgca ggaggcagaa ctggaaaagc tgaaaatggc 720tgcaaaacct atgctgccct ccagcttcag tctccctttc cccatcagct cgcccctgca 780ggcagcgtcc atatatggag catcctaccc gttccataga cctgtgcttc ccatcccgcc 840tgtgggactc tatgccacgc cagtgggata tggcatgtac cacctgtcct aaggaagacc 900agatcaatag actccatgat ggatgcttgt ttcaaagggt ttcctctccc tctccacgaa 960ggcagtacca gccagtactc ctgctctgct aaccctgcgt gcaccaccct aagcggctag 1020gctgacaggg ccacacgaca tagctgaaat ttgttctgta ggcggaggca ccaagccctg 1080ttttcttggt gtaatcttcc agatgccccc ttttcctttc acaaagattg gctctgatgg 1140tttttatgta taaatatata tatataataa aatataatac atttttatac agcagacgta 1200aaaattcaaa ttattttaaa aggcaaaatt tatatacata tgtgcttttt ttctatatct 1260caccttccca aaagacactg tgtaagtcca tttgttgtat tttcttaaag agggagacaa 1320attatttgca aaatgtgcta aagtcaatga tttttacggg attattgact tctgcttatg 1380gaaaacaaag aaacagacac aatgcacaca gaaaatatta gatatggaga gattattcaa 1440agtgaagggg acacatcata tttctgcatt ttacttgcat taaaagaaac ctctttatat 1500actacagttg ttcctatctc tcccccgccc cccaccgccc caccacacac atatttttaa 1560agtttttcct tttttaagaa tatttttgta agaccaatac ctgggatgag aagaatcctg 1620agactgcctg gaggtgaggt agaaaattag aaatacttcc taattcttct caaggctgtt 1680ggtaacttta tttcagataa ttggagagta aaatgttaaa acctgttgag aggaattgat 1740ggtttctgag aaatactagg tacattcatc ctcacagatt gcaaaggtga tttgggtggg 1800ggtttagtaa ttttctgctt aaaaaatgag tatcttgtaa ccattaccta tatgctaaat 1860attcttgaac aattagtaga tccagaaaga aaaaaaaata tgctttctct gtgtgtgtac 1920ctgttgtatg tcctaaactt attagaaaat tttatatact tttttacatg ttggggggca 1980gaaggtaaag ccatgttttg acttggtgaa aatgggattg tcaaacagcc cattaagttc 2040cctggtattt caccttcctg tccatctgtc ccctccctcc ggtatacctt tatccctttg 2100aaagggtgct tgtacaattt gatatatttt attgaagagt tatctcttat tctgaattaa 2160attaagcatt tgttttattg cagtaaagtt tgtccaaact cacaattaaa aaaaaaaaaa 2220aaaa 2224442379DNAHomo sapiens 44gacccccgag ctgtgctgct cgcggccgcc accgccgggc cccggccgtc cctggctccc 60ctcctgcctc gagaagggca gggcttctca gaggcttggc gggaaaaaga acggagggag 120ggatcgcgct gagtataaaa gccggttttc ggggctttat ctaactcgct gtagtaattc 180cagcgagagg cagagggagc gagcgggcgg ccggctaggg tggaagagcc gggcgagcag 240agctgcgctg cgggcgtcct gggaagggag atccggagcg aatagggggc ttcgcctctg 300gcccagccct cccgctgatc ccccagccag cggtccgcaa cccttgccgc atccacgaaa 360ctttgcccat agcagcgggc gggcactttg cactggaact tacaacaccc gagcaaggac 420gcgactctcc cgacgcgggg aggctattct gcccatttgg ggacacttcc ccgccgctgc 480caggacccgc ttctctgaaa ggctctcctt gcagctgctt agacgctgga tttttttcgg 540gtagtggaaa accagcagcc tcccgcgacg atgcccctca acgttagctt caccaacagg 600aactatgacc tcgactacga ctcggtgcag ccgtatttct actgcgacga ggaggagaac 660ttctaccagc agcagcagca gagcgagctg cagcccccgg cgcccagcga ggatatctgg 720aagaaattcg agctgctgcc caccccgccc ctgtccccta gccgccgctc cgggctctgc 780tcgccctcct acgttgcggt cacacccttc tcccttcggg gagacaacga cggcggtggc 840gggagcttct ccacggccga ccagctggag atggtgaccg agctgctggg aggagacatg 900gtgaaccaga gtttcatctg cgacccggac gacgagacct tcatcaaaaa catcatcatc 960caggactgta tgtggagcgg cttctcggcc gccgccaagc tcgtctcaga gaagctggcc 1020tcctaccagg ctgcgcgcaa agacagcggc agcccgaacc ccgcccgcgg ccacagcgtc 1080tgctccacct ccagcttgta cctgcaggat ctgagcgccg ccgcctcaga gtgcatcgac 1140ccctcggtgg tcttccccta ccctctcaac gacagcagct cgcccaagtc ctgcgcctcg 1200caagactcca gcgccttctc tccgtcctcg gattctctgc tctcctcgac ggagtcctcc 1260ccgcagggca gccccgagcc cctggtgctc catgaggaga caccgcccac caccagcagc 1320gactctgagg aggaacaaga agatgaggaa gaaatcgatg ttgtttctgt ggaaaagagg 1380caggctcctg gcaaaaggtc agagtctgga tcaccttctg ctggaggcca cagcaaacct 1440cctcacagcc cactggtcct caagaggtgc cacgtctcca cacatcagca caactacgca 1500gcgcctccct ccactcggaa ggactatcct gctgccaaga gggtcaagtt ggacagtgtc 1560agagtcctga gacagatcag caacaaccga aaatgcacca gccccaggtc ctcggacacc 1620gaggagaatg tcaagaggcg aacacacaac gtcttggagc gccagaggag gaacgagcta 1680aaacggagct tttttgccct gcgtgaccag atcccggagt tggaaaacaa tgaaaaggcc 1740cccaaggtag ttatccttaa aaaagccaca gcatacatcc tgtccgtcca agcagaggag 1800caaaagctca tttctgaaga ggacttgttg cggaaacgac gagaacagtt gaaacacaaa 1860cttgaacagc tacggaactc ttgtgcgtaa ggaaaagtaa ggaaaacgat tccttctaac 1920agaaatgtcc tgagcaatca cctatgaact tgtttcaaat gcatgatcaa atgcaacctc 1980acaaccttgg ctgagtcttg agactgaaag atttagccat aatgtaaact gcctcaaatt 2040ggactttggg cataaaagaa cttttttatg cttaccatct tttttttttc tttaacagat 2100ttgtatttaa gaattgtttt taaaaaattt taagatttac acaatgtttc tctgtaaata 2160ttgccattaa atgtaaataa ctttaataaa acgtttatag cagttacaca gaatttcaat 2220cctagtatat agtacctagt attataggta ctataaaccc taattttttt tatttaagta 2280cattttgctt tttaaagttg atttttttct attgttttta gaaaaaataa aataactggc 2340aaatatatca ttgagccaaa tcttaaaaaa aaaaaaaaa 2379451669DNAHomo sapiens 45gctcctgtca tcgaggcccc tggcccaatg gcaggctgag tccccctcct ctggcctggt 60cccgcctctc ctgccccttg tgctcagcgc tacctgctgc ccggacacat ccagagctgg 120ccgacgggtg cgcgggcggg cggcggcacc atgcagggaa gctgccaggg gccgtgggca 180gcgccgcttt ctgccgccca cctggcgctg tgagactggc gctgccacca tgttccccag 240ccctgctctc acgcccacgc ccttctcagt caaagacatc ctaaacctgg aacagcagca 300gcgcagcctg gctgccgccg gagagctctc tgcccgcctg gaggcgaccc tggcgccctc 360ctcctgcatg ctggccgcct tcaagccaga ggcctacgct gggcccgagg cggctgcgcc 420gggcctccca gagctgcgcg cagagctggg ccgcgcgcct tcaccggcca agtgtgcgtc 480tgcctttccc gccgcccccg ccttctatcc acgtgcctac agcgaccccg acccagccaa 540ggaccctaga gccgaaaaga aagagctgtg cgcgctgcag aaggcggtgg agctggagaa 600gacagaggcg gacaacgcgg agcggccccg ggcgcgacgg cggaggaagc cgcgcgtgct 660cttctcgcag gcgcaggtct atgagctgga gcggcgcttc aagcagcagc ggtacctgtc 720ggcccccgaa cgcgaccagc tggccagcgt gctgaaactc acgtccacgc aggtcaagat 780ctggttccag aaccggcgct acaagtgcaa gcggcagcgg caggaccaga ctctggagct 840ggtggggctg cccccgccgc cgccgccgcc tgcccgcagg atcgcggtgc cagtgctggt 900gcgcgatggc aagccatgcc taggggactc ggcgccctac gcgcctgcct acggcgtggg 960cctcaatccc tacggttata acgcctaccc cgcctatccg ggttacggcg gcgcggcctg 1020cagccctggc tacagctgca ctgccgctta ccccgccggg ccttccccag cgcagccggc 1080cactgccgcc gccaacaaca acttcgtgaa cttcggcgtc ggggacttga atgcggttca 1140gagccccggg attccgcaga gcaactcggg agtgtccacg ctgcatggta tccgagcctg 1200gtagggaagg gacccgcgtg gcgcgaccct gaccgatccc acctcaacag ctccctgact 1260ctcgggggga gaaggggctc ccaacatgac cctgagtccc ctggattttg cattcactcc 1320tgcggagacc taggaacttt ttctgtccca cgcgcgtttg ttcttgcgca cgggagagtt 1380tgtggcggcg attatgcagc gtgcaatgag tgatcctgca gcctggtgtc ttagctgtcc 1440ccccaggagt gccctccgag agtccatggg cacccccggt tggaactggg actgagctcg 1500ggcacgcagg gcctgagatc tggccgccca ttccgcgagc cagggccggg cgcccgggcc 1560tttgctatct cgccgtcgcc cgcccacgca cccacccgta tttatgtttt tacctattgc 1620tgtaagaaat gacgatcccc ttcccattaa agagagtgcg ttgaccccg 1669462086DNAHomo sapiens 46ataagggctg gaggtgctgc tttcaggcct ggccagccca ccatgcacgc ccactgcctg 60cccttccttc tgcacgcctg gtgggcccta ctccaggcgg gtgctgcgac ggtggccact 120gcgctcctgc gtacgcgggg gcagccctcg tcgccatccc ctctggcgta catgctgagc 180ctctaccgcg acccgctgcc gagggcagac atcatccgca gcctacaggc agaagatgtg 240gcagtggatg ggcagaactg gacgtttgct tttgacttct ccttcctgag ccaacaagag 300gatctggcat gggctgagct ccggctgcag ctgtccagcc ctgtggacct ccccactgag 360ggctcacttg ccattgagat tttccaccag ccaaagcccg acacagagca ggcttcagac 420agctgcttag agcggtttca gatggaccta ttcactgtca ctttgtccca ggtcaccttt 480tccttgggca gcatggtttt ggaggtgacc aggcctctct ccaagtggct gaagcaccct 540ggggccctgg agaagcagat gtccagggta gctggagagt gctggccgcg gccccccaca 600ccgcctgcca ccaatgtgct ccttatgctc tactccaacc tctcgcagga gcagaggcag 660ctgggtgggt ccaccttgct gtgggaagcc gagagctcct ggcgggccca ggagggacag 720ctgtcctggg agtggggcaa gaggcaccgt cgacatcact tgccagacag aagtcaactg 780tgtcggaagg tcaagttcca ggtggacttc aacctgatcg gatggggctc ctggatcatc 840taccccaagc agtacaacgc ctatcgctgt gagggcgagt gtcctaatcc tgttggggag 900gagtttcatc cgaccaacca tgcatacatc cagagtctgc tgaaacgtta ccagccccac 960cgagtccctt ccacttgttg tgccccagtg aagaccaagc cgctgagcat gctgtatgtg 1020gataatggca gagtgctcct agatcaccat aaagacatga tcgtggaaga atgtgggtgc 1080ctctgatgac atcctggagg gagactggat ttgcctgcac tctggaaggc tgggaaactc 1140ctggaagaca tgataaccat ctaatccagt aaggagaaac agagaggggc aaagttgctc 1200tgcccaccag aactgaagag gaggggctgc ccactctgta aatgaagggc tcagtggagt 1260ctggccaagc acagaggctg ctgtcaggaa gagggaggaa gaagcctgtg cagggggctg 1320gctggatgtt ctctttactg aaaagacagt ggcaaggaaa agcacaagtg catgagttct 1380ttactggatt ttttaaaaac ctgtgaaccc cccgaaactg tatgtgaaag ttgagacata 1440tgtgcatgta ttttggaggt gggatgaagt cacctatagc tttcatgtat tctccaaagt 1500agtctgtgtg tgacctgtcc ccctccccaa agattaagga tcactgtata gattaaaaag 1560agtccgtcaa tctcattgcc tcaggctggg ttgggggagc cccacagctt tctggctggc 1620cagtggcaat ctactggcct tgtccagagg ctcactggag tggttctctg ctaatgagct 1680gtacaacaat aaagccattg tctagttctc ctgggccagc tggtgcctgt gaaggcagag 1740gcaggaactc atccaagagg accggccatg ttgggttaca gaagacatcc ctgcgtcagt 1800ctgcttcggc agacacagcc tgagtttgtt aaagttggtg acaatccacc tcagtctctc 1860aatgtgtgct attaatgagg cctctgagct tcctatccag cagtggtgaa ggccttgccc 1920tgggtggcaa gatacttgct ctatggtcac agctcagcca ctggaagctg tgcgacctca 1980ggtgagcaat tcactgtcca gtctccactt gtaaaaggaa cgctggtgaa tcctaatgca 2040ttcatattaa atgtctgttg tcaggctcag aagagccatg agcttt 2086473039DNAHomo sapiens 47aataaagcgt gaacccgtcc gtccggctcg cactttaaga cttcccgagc ggcggcgggg 60acgccagtcg agccgggaga cgcttacctg ccgcttcccc gcgccgcccg gtgcacctgg 120ccgcaaggga cctcgttctc agggaagacg gcgacattcc gcggaggtgg aaccgccgcg 180cgccgtccgg gctcggacct tccccggaac gtgggggcgc cttagcgact ccttccctgt 240tgtgcccccg ttcccggcgt tcagcccggc cccgcaaagg tgggacggct cccggcttca 300gttacggaag cggcccgtgt ccagcgacga gggttcgaaa atgccccgcg cgttcctggt 360gaagaagccg tgcgtctcca cgtgcaagag gaactggagc gagctccccg acgaggagcg 420cggcgagatc tacgtgccag tcagcctggg cttctgccca ccacagccct accgggagcc 480ggaaccctct gtggccgaac ccccttcctg cccgctggct ttgaacatga gccttcgaga 540ctctagctac agcatggccc ccgggccctg tgtggtggcc cagctgccct ctgaagacat 600gggccacttg acagaccccc agagcagaga ccatggcttc ctgcgcacca agatgaaggt 660gacccttggg gacagtccca gtggagacct gttcacctgc cgtgtctgcc agaaggcctt 720cacctaccag cgcatgctga accgccacat gaagtgtcac aacgacgtca agaggcacct 780ctgcacgtac tgcgggaagg gcttcaatga caccttcgac ctcaagagac acgtccgaac 840tcacactggc gtgcggccct acaagtgcag cctgtgtgac aaggccttca cgcagcgctg 900ctctctggag tctcacctca agaagatcca tggtgtgcag cagaagtacg cgtacaagga 960gcggcgggcc aagctgtacg tgtgtgagga gtgcggctgc acatctgaga gccaggaggg 1020ccacgtcctg cacctgaagg agcaccaccc tgacagcccg ctgctgcgca agacctccaa 1080gaaggtggcc gtggcactac

agaacactgt cacttccctg ctgcagggca gcccccacct 1140gtgagtggct cgagccctgg gggtgctcct ggaagcccca agagcatcca ggattgcctc 1200ccagctgcct ggccagccca ccctcctgca acctctcacc cgaacaccag tgatcaggac 1260tggagccccc gtgccttggt ctcccccctg ggcacacgtg ctcactcagg cccagcaatg 1320acctctgctc atttttgcat ttttgactta tgggccgagg ctgttctgag cctgggaaga 1380tgtacctatg tcaagagaag ggatgaggcc aaggctgcct tcaattagaa gcagccgccc 1440acagagacag gcactgtgtg cctggcagca ggacttccta cccagaggag gttcgagcta 1500ggatcccact gcccccgcct ctcagcacag ggcaggggct gcaggtcccc agtggacatc 1560agagtcaaaa gcactggcaa agggtacccc tgcaaacaac tgtggtgggg gctggcagca 1620gaccccccac ctggcagggc ttctaatgct cagggttctg gagggctctg tccttccggc 1680aaggagaggc acacatgtgt gcccagccgt gtgtgtgcgt gtgcttgtgt gtgtgcactg 1740ctgtgtgtgt gtgcacgcac aggaagcctt tccacatatc acctcatttc taagaaataa 1800actacaaggt gccaagaagg ttttatttcc ttttattttt taaagatgac aaatgtacag 1860atgttaatat atttttggtg ccaatggcga tgtttttaag agtgggatgg agctggcttt 1920tctccattcc cgtgcgcttc tatttatcct ggacatttca aacctcctct gtgccttggc 1980tctgggcggg ggctgcccca acccaccccc gttctttgta cgtgctgaga cagccactag 2040aagatcttcc tccagcggcg ccctggacgg ctgctcctgc gaacagccca tggcatcttc 2100tgctcttccc tcccggctct gccctgcaca tcctgttgag ccaagcccca gtgacccgga 2160gagctggcct gatgctgaga gtgtgtcctc ctggggcttt agggggcagg aaggtgggac 2220gaatgacgat gcccatccac tacctgaagc actaggacac tcttgcaggg ccaggctgga 2280agaccggccc ttttcttggt tgagtcaaaa gccttagcac agtggcaaaa aatgggacag 2340aatgatgacc agcacctcag aaacttccag agggaggaga ggatttgatg gctaccaaat 2400tgtatctgtt gccttttttc tgactttttc acctgaccag gctggggttt ggagtggctg 2460tggggagacc cgtcctggct ggctggctgg ctcccttgct cccttgctgc agctgggaaa 2520ggggttctgg gtgtaaagag gtgtgcgtct tgtgggccaa agggaaaaac aggcaggggt 2580cagagccagc ctgccagagg caaatgcaaa agaggtcccc agaacacagc cagctgggca 2640gccccttaaa gccaaacccc acctgaagca gaaccacttt ggcctcccct gcccaaaatg 2700ggtagtgtct acacgtcccc gggctcaggc tcaggcccag ccctgggctg acctgagagg 2760aaggctcctt cctggactgc cctctgaaat gtgtatagat tgattctaaa atctcttgtt 2820tcacttgact ttagagtgtc tgggacgctg ctgtattctg aaagtcacat agcacacagt 2880aatgttatct ggaagctctg tttttgttta catttctgta tccctgggtt gactgccaat 2940ccgaggccgt catgaagctc tgtgttgtct gttttatttt ataaccttcc tctcaactat 3000taaaattaga gatctaatgt ttaaaaaaaa aaaaaaaaa 3039483393DNAHomo sapiens 48cctgcctgcc tccctgcgca cccgcagcct cccccgctgc ctccctaggg ctcccctccg 60gccgccagcg cccatttttc attccctaga tagagatact ttgcgcgcac acacatacat 120acgcgcgcaa aaaggaaaaa aaaaaaaaaa agcccaccct ccagcctcgc tgcaaagaga 180aaaccggagc agccgcagct cgcagctcgc agctcgcagc ccgcagcccg cagaggacgc 240ccagagcggc gagcgggcgg gcagacggac cgacggactc gcgccgcgtc cacctgtcgg 300ccgggcccag ccgagcgcgc agcgggcacg ccgcgcgcgc ggagcagccg tgcccgccgc 360ccgggccccg cgccagggcg cacacgctcc cgccccccta cccggcccgg gcgggagttt 420gcacctctcc ctgcccgggt gctcgagctg ccgttgcaaa gccaactttg gaaaaagttt 480tttgggggag acttgggcct tgaggtgccc agctccgcgc tttccgattt tgggggcctt 540tccagaaaat gttgcaaaaa agctaagccg gcgggcagag gaaaacgcct gtagccggcg 600agtgaagacg aaccatcgac tgccgtgttc cttttcctct tggaggttgg agtcccctgg 660gcgcccccac acggctagac gcctcggctg gttcgcgacg cagccccccg gccgtggatg 720ctcactcggg ctcgggatcc gcccaggtag cggcctcgga cccaggtcct gcgcccaggt 780cctcccctgc cccccagcga cggagccggg gccgggggcg gcggcgcccg ggggccatgc 840gggtgagccg cggctgcaga ggcctgagcg cctgatcgcc gcggacccga gccgagccca 900cccccctccc cagcccccca ccctggccgc gggggcggcg cgctcgatct acgcgtccgg 960ggccccgcgg ggccgggccc ggagtcggca tgaatcgctg ctgggcgctc ttcctgtctc 1020tctgctgcta cctgcgtctg gtcagcgccg agggggaccc cattcccgag gagctttatg 1080agatgctgag tgaccactcg atccgctcct ttgatgatct ccaacgcctg ctgcacggag 1140accccggaga ggaagatggg gccgagttgg acctgaacat gacccgctcc cactctggag 1200gcgagctgga gagcttggct cgtggaagaa ggagcctggg ttccctgacc attgctgagc 1260cggccatgat cgccgagtgc aagacgcgca ccgaggtgtt cgagatctcc cggcgcctca 1320tagaccgcac caacgccaac ttcctggtgt ggccgccctg tgtggaggtg cagcgctgct 1380ccggctgctg caacaaccgc aacgtgcagt gccgccccac ccaggtgcag ctgcgacctg 1440tccaggtgag aaagatcgag attgtgcgga agaagccaat ctttaagaag gccacggtga 1500cgctggaaga ccacctggca tgcaagtgtg agacagtggc agctgcacgg cctgtgaccc 1560gaagcccggg gggttcccag gagcagcgag ccaaaacgcc ccaaactcgg gtgaccattc 1620ggacggtgcg agtccgccgg ccccccaagg gcaagcaccg gaaattcaag cacacgcatg 1680acaagacggc actgaaggag acccttggag cctaggggca tcggcaggag agtgtgtggg 1740cagggttatt taatatggta tttgctgtat tgcccccatg gggtccttgg agtgataata 1800ttgtttccct cgtccgtctg tctcgatgcc tgattcggac ggccaatggt gcttccccca 1860cccctccacg tgtccgtcca cccttccatc agcgggtctc ctcccagcgg cctccggcgt 1920cttgcccagc agctcaagaa gaaaaagaag gactgaactc catcgccatc ttcttccctt 1980aactccaaga acttgggata agagtgtgag agagactgat ggggtcgctc tttgggggaa 2040acgggctcct tcccctgcac ctggcctggg ccacacctga gcgctgtgga ctgtcctgag 2100gagccctgag gacctctcag catagcctgc ctgatccctg aacccctggc cagctctgag 2160gggaggcacc tccaggcagg ccaggctgcc tcggactcca tggctaagac cacagacggg 2220cacacagact ggagaaaacc cctcccacgg tgcccaaaca ccagtcacct cgtctccctg 2280gtgcctctgt gcacagtggc ttcttttcgt tttcgttttg aagacgtgga ctcctcttgg 2340tgggtgtggc cagcacacca agtggctggg tgccctctca ggtgggttag agatggagtt 2400tgctgttgag gtggctgtag atggtgacct gggtatcccc tgcctcctgc caccccttcc 2460tccccacact ccactctgat tcacctcttc ctctggttcc tttcatctct ctacctccac 2520cctgcatttt cctcttgtcc tggcccttca gtctgctcca ccaaggggct cttgaacccc 2580ttattaaggc cccagatgat cccagtcact cctctctagg gcagaagact agaggccagg 2640gcagcaaggg acctgctcat catattccaa cccagccacg actgccatgt aaggttgtgc 2700agggtgtgta ctgcacaagg acattgtatg cagggagcac tgttcacatc atagataaag 2760ctgatttgta tatttattat gacaatttct ggcagatgta ggtaaagagg aaaaggatcc 2820ttttcctaat tcacacaaag actccttgtg gactggctgt gcccctgatg cagcctgtgg 2880cttggagtgg ccaaatagga gggagactgt ggtaggggca gggaggcaac actgctgtcc 2940acatgacctc catttcccaa agtcctctgc tccagcaact gcccttccag gtgggtgtgg 3000gacacctggg agaaggtctc caagggaggg tgcagccctc ttgcccgcac ccctccctgc 3060ttgcacactt ccccatcttt gatccttctg agctccacct ctggtggctc ctcctaggaa 3120accagctcgt gggctgggaa tgggggagag aagggaaaag atccccaaga ccccctgggg 3180tgggatctga gctcccacct cccttcccac ctactgcact ttcccccttc ccgccttcca 3240aaacctgctt ccttcagttt gtaaagtcgg tgattatatt tttgggggct ttccttttat 3300tttttaaatg taaaatttat ttatattccg tatttaaagt tgtaaaaaaa aataaccaca 3360aaacaaaacc aaatgaaaaa aaaaaaaaaa aaa 3393494934DNAHomo sapiens 49aaacccgatc tccttggact tgaatgagga ggaggaggcg gcggcggcgg cggcggcgga 60ggcgctcggc tggggaaagc tagcggcaga ggctcagccc cggcggcagc gcgcgccccg 120ctgccagccc attttccgga cgccacccgc gggcactgcc gacgcccccg gggctgccga 180ggggaggccg ggggggcgca gcggagcgcg gtcccgcgca ctgagccccg cggcgccccg 240ggaacttggc ggcgacccga gcccggcgag ccggggcgcg cctcccccgc cgcgcgcctc 300ctgcatgcgg ggccccagct ccgggcgccg gccggagccc cccccggccg cccccgagcc 360ccccgcgccc cgcgccgcgc cgccgcgccg tccatgcacc gcttgatggg ggtcaacagc 420accgccgccg ccgccgccgg gcagcccaat gtctcctgca cgtgcaactg caaacgctct 480ttgttccaga gcatggagat cacggagctg gagtttgttc agatcatcat catcgtggtg 540gtgatgatgg tgatggtggt ggtgatcacg tgcctgctga gccactacaa gctgtctgca 600cggtccttca tcagccggca cagccagggg cggaggagag aagatgccct gtcctcagaa 660ggatgcctgt ggccctcgga gagcacagtg tcaggcaacg gaatcccaga gccgcaggtc 720tacgccccgc ctcggcccac cgaccgcctg gccgtgccgc ccttcgccca gcgggagcgc 780ttccaccgct tccagcccac ctatccgtac ctgcagcacg agatcgacct gccacccacc 840atctcgctgt cagacgggga ggagccccca ccctaccagg gcccctgcac cctccagctt 900cgggaccccg agcagcagct ggaactgaac cgggagtcgg tgcgcgcacc cccaaacaga 960accatcttcg acagtgacct gatggatagt gccaggctgg gcggcccctg cccccccagc 1020agtaactcgg gcatcagcgc cacgtgctac ggcagcggcg ggcgcatgga ggggccgccg 1080cccacctaca gcgaggtcat cggccactac ccggggtcct ccttccagca ccagcagagc 1140agtgggccgc cctccttgct ggaggggacc cggctccacc acacacacat cgcgccccta 1200gagagcgcag ccatctggag caaagagaag gataaacaga aaggacaccc tctctagggt 1260ccccaggggg gccgggctgg ggctgcgtag gtgaaaaggc agaacactcc gcgcttctta 1320gaagaggagt gagaggaagg cggggggcgc agcaacgcat cgtgtggccc tcccctccca 1380cctccctgtg tataaatatt tacatgtgat gtctggtctg aatgcacaag ctaagagagc 1440ttgcaaaaaa aaaaagaaaa aagaaaaaaa aaaaccacgt ttctttgttg agctgtgtct 1500tgaaggcaaa agaaaaaaaa tttctacagt agtctttctt gtttctagtt gagctgcgtg 1560cgtgaatgct tattttcttt tgtttatgat aatttcactt aactttaaag acatatttgc 1620acaaaacctt tgtttaaaga tctgcaatat tatatatata aatatatata agataagaga 1680aactgtatgt gcgagggcag gagtattttt gtattagaag aggcctatta aaaaaaaaag 1740ttgttttctg aactagaaga ggaaaaaaat ggcaattttt gagtgccaag tcagaaagtg 1800tgtattacct tgtaaagaaa aaaattacaa agcaggggtt tagagttatt tatataaatg 1860ttgagatttt gcactatttt ttaatataaa tatgtcagtg cttgcttgat ggaaacttct 1920cttgtgtctg ttgagacttt aagggagaaa tgtcggaatt tcagagtcgc ctgacggcag 1980agggtgagcc cccgtggagt ctgcagagag gccttggcca ggagcggcgg gctttcccga 2040ggggccactg tccctgcaga gtggatgctt ctgcctagtg acaggttatc accacgttat 2100atattcccta ccgaaggaga caccttttcc cccctgaccc agaacagcct ttaaatcaca 2160agcaaaatag gaaagttaac cacggaggca ccgagttcca ggtagtggtt ttgcctttcc 2220caaaaatgaa aataaactgt taccgaagga attagttttt cctcttcttt tttccaactg 2280tgaaggtccc cgtggggtgg agcatggtgc ccctcacaag ccgcagcggc tggtgcccgg 2340gctaccaggg acatgccaga gggctcgatg acttgtctct gcagggcgct ttggtggttg 2400ttcagctggc taaaggttca ccggtgaagg caggtgcggt aactgccgca ctggacccta 2460ggaagcccca ggtattcgca atctgacctc ctcctgtctg tttcccttca cggatcaatt 2520ctcacttaag aggccaataa acaacccaac atgaaaaggt gacaagcctg ggtttctccc 2580aggataggtg aaagggttaa aatgagtaaa gcagttgagc aaacaccaac ccgagcttcg 2640ggcgcagaat tcttcacctt ctcttcccct ttccatctcc tttccccgcg gaaacaacgc 2700ttcccttctg gtgtgtctgt tgatctgtgt tttcatttac atctctctta gactccgctc 2760ttgttctcca ggttttcacc agatagattt ggggttggcg ggacctgctg gtgacgtgca 2820ggtgaaggac aggaaggggc atgtgagcgt aaatagaggt gaccagagga gagcatgagg 2880ggtggggctt tgggacccac cggggccagt ggctggagct tgacgtcttt cctccccatg 2940ggggtgggag ggcccccagc tggaagagca gactcccagc tgctaccccc tcccttccca 3000tgggagtggc tttccatttt gggcagaatg ctgactagta gactaacata aaagatataa 3060aaggcaataa ctattgtttg tgagcaactt ttttataact tccaaaacaa aaacctgagc 3120acagttttga agttctagcc actcgagctc atgcatgtga aacgtgtgct ttacgaaggt 3180ggcagctgac agacgtgggc tctgcatgcc gccagcctag tagaaagttc tcgttcattg 3240gcaacagcag aacctgcctc tccgtgaagt cgtcagccta aaatttgttt ctctcttgaa 3300gaggattctt tgaaaaggtc ctgcagagaa atcagtacag gttatcccga aaggtacaag 3360gacgcacttg taaagatgat taaaacgtat ctttccttta tgtgacgcgt ctctagtgcc 3420ttactgaaga agcagtgaca ctcccgtcgc tcggtgagga cgttcccgga cagtgcctca 3480ctcacctggg actggtatcc cctcccaggg tccaccaagg gctcctgctt ttcagacacc 3540ccatcatcct cgcgcgtcct caccctgtct ctaccaggga ggtgcctagc ttggtgaggt 3600tactcctgct cctccaacct ttttttgcca aggtttgtac acgactccca tctaggctga 3660aaacctagaa gtggaccttg tgtgtgtgca tggtgtcagc ccaaagccag gctgagacag 3720tcctcatatc ctcttgagcc aaactgtttg ggtctcgttg cttcatggta tggtctggat 3780ttgtgggaat ggctttgcgt gagaaagggg aggagagtgg ttgctgccct cagccggctt 3840gaggacagag cctgtccctc tcatgacaac tcagtgttga agcccagtgt cctcagcttc 3900atgtccagtg gatggcagaa gttcatgggg tagtggcctc tcaaaggctg ggcgcatccc 3960aagacagcca gcaggttgtc tctggaaacg accagagtta agctctcggc ttctctgctg 4020agggtgcacc ctttcctcta gatggtagtt gtcacgttat ctttgaaaac tcttggactg 4080ctcctgagga ggccctcttt tccagtagga agttagatgg gggttctcag aagtggctga 4140ttggaagggg acaagcttcg tttcaggggt ctgccgttcc atcctggttc agagaaggcc 4200gagcgtggct ttctctagcc ttgtcactgt ctccctgcct gtcaatcacc acctttcctc 4260cagaggagga aaattatctc ccctgcaaag cccggttcta cacagatttc acaaattgtg 4320ctaagaaccg tccgtgttct cagaaagccc agtgtttttg caaagaatga aaagggaccc 4380catatgtagc aaaaatcagg gctgggggag agccgggttc attccctgtc ctcattggtc 4440gtccctatga attgtacgtt tcagagaaat tttttttcct atgtgcaaca cgaagcttcc 4500agaaccataa aatatcccgt cgataaggaa agaaaatgtc gttgttgttg tttttctgga 4560aactgcttga aatcttgctg tactatagag ctcagaagga cacagcccgt cctcccctgc 4620ctgcctgatt ccatggctgt tgtgctgatt ccaatgcttt cacgttggtt cctggcgtgg 4680gaactgctct cctttgcagc cccatttccc aagctctgtt caagttaaac ttatgtaagc 4740tttccgtggc atgcggggcg cgcacccacg tccccgctgc gtaagactct gtatttggat 4800gccaatccac aggcctgaag aaactgcttg ttgtgtatca gtaatcatta gtggcaatga 4860tgacattctg aaaagctgca atacttatac aataaatttt acaattcttt ggaatgagaa 4920aaaaaaaaaa aaaa 4934501818DNAHomo sapiens 50ggcgcccgcg cccgcccccg cgccgggccc ggctcggccc gacccggctc cgccgcgggc 60aggcggggcc cagcgcactc ggagcccgag cccgagccgc agccgccgcc tggggcgctt 120gggtcggcct cgaggacacc ggagaggggc gccacgccgc cgtggccgca gaaatgacca 180tggttgacac agagatgcca ttctggccca ccaactttgg gatcagctcc gtggatctct 240ccgtaatgga agaccactcc cactcctttg atatcaagcc cttcactact gttgacttct 300ccagcatttc tactccacat tacgaagaca ttccattcac aagaacagat ccagtggttg 360cagattacaa gtatgacctg aaacttcaag agtaccaaag tgcaatcaaa gtggagcctg 420catctccacc ttattattct gagaagactc agctctacaa taagcctcat gaagagcctt 480ccaactccct catggcaatt gaatgtcgtg tctgtggaga taaagcttct ggatttcact 540atggagttca tgcttgtgaa ggatgcaagg gtttcttccg gagaacaatc agattgaagc 600ttatctatga cagatgtgat cttaactgtc ggatccacaa aaaaagtaga aataaatgtc 660agtactgtcg gtttcagaaa tgccttgcag tggggatgtc tcataatgcc atcaggtttg 720ggcggatgcc acaggccgag aaggagaagc tgttggcgga gatctccagt gatatcgacc 780agctgaatcc agagtccgct gacctccggg ccctggcaaa acatttgtat gactcataca 840taaagtcctt cccgctgacc aaagcaaagg cgagggcgat cttgacagga aagacaacag 900acaaatcacc attcgttatc tatgacatga attccttaat gatgggagaa gataaaatca 960agttcaaaca catcaccccc ctgcaggagc agagcaaaga ggtggccatc cgcatctttc 1020agggctgcca gtttcgctcc gtggaggctg tgcaggagat cacagagtat gccaaaagca 1080ttcctggttt tgtaaatctt gacttgaacg accaagtaac tctcctcaaa tatggagtcc 1140acgagatcat ttacacaatg ctggcctcct tgatgaataa agatggggtt ctcatatccg 1200agggccaagg cttcatgaca agggagtttc taaagagcct gcgaaagcct tttggtgact 1260ttatggagcc caagtttgag tttgctgtga agttcaatgc actggaatta gatgacagcg 1320acttggcaat atttattgct gtcattattc tcagtggaga ccgcccaggt ttgctgaatg 1380tgaagcccat tgaagacatt caagacaacc tgctacaagc cctggagctc cagctgaagc 1440tgaaccaccc tgagtcctca cagctgtttg ccaagctgct ccagaaaatg acagacctca 1500gacagattgt cacggaacac gtgcagctac tgcaggtgat caagaagacg gagacagaca 1560tgagtcttca cccgctcctg caggagatct acaaggactt gtactagcag agagtcctga 1620gccactgcca acatttccct tcttccagtt gcactattct gagggaaaat ctgacaccta 1680agaaatttac tgtgaaaaag cattttaaaa agaaaaggtt ttagaatatg atctatttta 1740tgcatattgt ttataaagac acatttacaa tttactttta atattaaaaa ttaccatatt 1800atgaaattgc tgatagta 1818514507DNAHomo sapiens 51gaccaattgt catacgactt gcagtgagcg tcaggagcac gtccaggaac tcctcagcag 60cgcctccttc agctccacag ccagacgccc tcagacagca aagcctaccc ccgcgccgcg 120ccctgcccgc cgctgcgatg ctcgcccgcg ccctgctgct gtgcgcggtc ctggcgctca 180gccatacagc aaatccttgc tgttcccacc catgtcaaaa ccgaggtgta tgtatgagtg 240tgggatttga ccagtataag tgcgattgta cccggacagg attctatgga gaaaactgct 300caacaccgga atttttgaca agaataaaat tatttctgaa acccactcca aacacagtgc 360actacatact tacccacttc aagggatttt ggaacgttgt gaataacatt cccttccttc 420gaaatgcaat tatgagttat gtgttgacat ccagatcaca tttgattgac agtccaccaa 480cttacaatgc tgactatggc tacaaaagct gggaagcctt ctctaacctc tcctattata 540ctagagccct tcctcctgtg cctgatgatt gcccgactcc cttgggtgtc aaaggtaaaa 600agcagcttcc tgattcaaat gagattgtgg aaaaattgct tctaagaaga aagttcatcc 660ctgatcccca gggctcaaac atgatgtttg cattctttgc ccagcacttc acgcatcagt 720ttttcaagac agatcataag cgagggccag ctttcaccaa cgggctgggc catggggtgg 780acttaaatca tatttacggt gaaactctgg ctagacagcg taaactgcgc cttttcaagg 840atggaaaaat gaaatatcag ataattgatg gagagatgta tcctcccaca gtcaaagata 900ctcaggcaga gatgatctac cctcctcaag tccctgagca tctacggttt gctgtggggc 960aggaggtctt tggtctggtg cctggtctga tgatgtatgc cacaatctgg ctgcgggaac 1020acaacagagt atgcgatgtg cttaaacagg agcatcctga atggggtgat gagcagttgt 1080tccagacaag caggctaata ctgataggag agactattaa gattgtgatt gaagattatg 1140tgcaacactt gagtggctat cacttcaaac tgaaatttga cccagaacta cttttcaaca 1200aacaattcca gtaccaaaat cgtattgctg ctgaatttaa caccctctat cactggcatc 1260cccttctgcc tgacaccttt caaattcatg accagaaata caactatcaa cagtttatct 1320acaacaactc tatattgctg gaacatggaa ttacccagtt tgttgaatca ttcaccaggc 1380aaattgctgg cagggttgct ggtggtagga atgttccacc cgcagtacag aaagtatcac 1440aggcttccat tgaccagagc aggcagatga aataccagtc ttttaatgag taccgcaaac 1500gctttatgct gaagccctat gaatcatttg aagaacttac aggagaaaag gaaatgtctg 1560cagagttgga agcactctat ggtgacatcg atgctgtgga gctgtatcct gcccttctgg 1620tagaaaagcc tcggccagat gccatctttg gtgaaaccat ggtagaagtt ggagcaccat 1680tctccttgaa aggacttatg ggtaatgtta tatgttctcc tgcctactgg aagccaagca 1740cttttggtgg agaagtgggt tttcaaatca tcaacactgc ctcaattcag tctctcatct 1800gcaataacgt gaagggctgt ccctttactt cattcagtgt tccagatcca gagctcatta 1860aaacagtcac catcaatgca agttcttccc gctccggact agatgatatc aatcccacag 1920tactactaaa agaacgttcg actgaactgt agaagtctaa tgatcatatt tatttattta 1980tatgaaccat gtctattaat ttaattattt aataatattt atattaaact ccttatgtta 2040cttaacatct tctgtaacag aagtcagtac tcctgttgcg gagaaaggag tcatacttgt 2100gaagactttt atgtcactac tctaaagatt ttgctgttgc tgttaagttt ggaaaacagt 2160ttttattctg ttttataaac cagagagaaa tgagttttga cgtcttttta cttgaatttc 2220aacttatatt ataagaacga aagtaaagat gtttgaatac ttaaacactg tcacaagatg 2280gcaaaatgct gaaagttttt acactgtcga tgtttccaat gcatcttcca tgatgcatta 2340gaagtaacta atgtttgaaa ttttaaagta cttttggtta tttttctgtc atcaaacaaa 2400aacaggtatc agtgcattat taaatgaata tttaaattag acattaccag taatttcatg 2460tctacttttt aaaatcagca atgaaacaat aatttgaaat ttctaaattc atagggtaga 2520atcacctgta aaagcttgtt tgatttctta aagttattaa acttgtacat ataccaaaaa 2580gaagctgtct tggatttaaa tctgtaaaat cagtagaaat tttactacaa ttgcttgtta 2640aaatatttta taagtgatgt tcctttttca ccaagagtat aaaccttttt agtgtgactg 2700ttaaaacttc cttttaaatc aaaatgccaa atttattaag gtggtggagc cactgcagtg

2760ttatcttaaa ataagaatat tttgttgaga tattccagaa tttgtttata tggctggtaa 2820catgtaaaat ctatatcagc aaaagggtct acctttaaaa taagcaataa caaagaagaa 2880aaccaaatta ttgttcaaat ttaggtttaa acttttgaag caaacttttt tttatccttg 2940tgcactgcag gcctggtact cagattttgc tatgaggtta atgaagtacc aagctgtgct 3000tgaataatga tatgttttct cagattttct gttgtacagt ttaatttagc agtccatatc 3060acattgcaaa agtagcaatg acctcataaa atacctcttc aaaatgctta aattcatttc 3120acacattaat tttatctcag tcttgaagcc aattcagtag gtgcattgga atcaagcctg 3180gctacctgca tgctgttcct tttcttttct tcttttagcc attttgctaa gagacacagt 3240cttctcatca cttcgtttct cctattttgt tttactagtt ttaagatcag agttcacttt 3300ctttggactc tgcctatatt ttcttacctg aacttttgca agttttcagg taaacctcag 3360ctcaggactg ctatttagct cctcttaaga agattaaaag agaaaaaaaa aggccctttt 3420aaaaatagta tacacttatt ttaagtgaaa agcagagaat tttatttata gctaatttta 3480gctatctgta accaagatgg atgcaaagag gctagtgcct cagagagaac tgtacggggt 3540ttgtgactgg aaaaagttac gttcccattc taattaatgc cctttcttat ttaaaaacaa 3600aaccaaatga tatctaagta gttctcagca ataataataa tgacgataat acttcttttc 3660cacatctcat tgtcactgac atttaatggt actgtatatt acttaattta ttgaagatta 3720ttatttatgt cttattagga cactatggtt ataaactgtg tttaagccta caatcattga 3780tttttttttg ttatgtcaca atcagtatat tttctttggg gttacctctc tgaatattat 3840gtaaacaatc caaagaaatg attgtattaa gatttgtgaa taaattttta gaaatctgat 3900tggcatattg agatatttaa ggttgaatgt ttgtccttag gataggccta tgtgctagcc 3960cacaaagaat attgtctcat tagcctgaat gtgccataag actgaccttt taaaatgttt 4020tgagggatct gtggatgctt cgttaatttg ttcagccaca atttattgag aaaatattct 4080gtgtcaagca ctgtgggttt taatattttt aaatcaaacg ctgattacag ataatagtat 4140ttatataaat aattgaaaaa aattttcttt tgggaagagg gagaaaatga aataaatatc 4200attaaagata actcaggaga atcttcttta caattttacg tttagaatgt ttaaggttaa 4260gaaagaaata gtcaatatgc ttgtataaaa cactgttcac tgtttttttt aaaaaaaaaa 4320cttgatttgt tattaacatt gatctgctga caaaacctgg gaatttgggt tgtgtatgcg 4380aatgtttcag tgcctcagac aaatgtgtat ttaacttatg taaaagataa gtctggaaat 4440aaatgtctgt ttatttttgt actatttaaa aattgacaga tcttttctga agaaaaaaaa 4500aaaaaaa 4507521331DNAHomo sapiens 52cctgcatctt tttggaagga ttctttttat aaatcagaaa gtgttcgagg ttcaaaggtt 60tgcctcggag cgtgtgaaca ttcctccgct cggttttcaa ctcgcctcca acctgcgccg 120cccggccagc atgtctcccc gcccgtgaag cggggctgcc gcctccctgc cgctccggct 180gccactaacg acccgccctc gccgccacct ggccctcctg atcgacgaca cacgcacttg 240aaacttgttc tcagggtgtg tggaatcaac tttccggaag caaccagccc accagaggag 300gtcccgagcg cgagcggaga cgatgcagcg gagactggtt cagcagtgga gcgtcgcggt 360gttcctgctg agctacgcgg tgccctcctg cgggcgctcg gtggagggtc tcagccgccg 420cctcaaaaga gctgtgtctg aacatcagct cctccatgac aaggggaagt ccatccaaga 480tttacggcga cgattcttcc ttcaccatct gatcgcagaa atccacacag ctgaaatcag 540agctacctcg gaggtgtccc ctaactccaa gccctctccc aacacaaaga accaccccgt 600ccgatttggg tctgatgatg agggcagata cctaactcag gaaactaaca aggtggagac 660gtacaaagag cagccgctca agacacctgg gaagaaaaag aaaggcaagc ccgggaaacg 720caaggagcag gaaaagaaaa aacggcgaac tcgctctgcc tggttagact ctggagtgac 780tgggagtggg ctagaagggg accacctgtc tgacacctcc acaacgtcgc tggagctcga 840ttcacggagg cattgaaatt ttcagcagag accttccaag gacatattgc aggattctgt 900aatagtgaac atatggaaag tattagaaat atttattgtc tgtaaatact gtaaatgcat 960tggaataaaa ctgtctcccc cattgctcta tgaaactgca cattggtcat tgtgaatatt 1020ttttttttgc caaggctaat ccaattatta ttatcacatt taccataatt tattttgtcc 1080attgatgtat ttattttgta aatgtatctt ggtgctgctg aatttctata ttttttgtaa 1140cataatgcac tttagatata catatcaagt atgttgataa atgacacaat gaagtgtctc 1200tattttgtgg ttgattttaa tgaatgccta aatataatta tccaaattga ttttcctttg 1260tgcatgtaaa aataacagta ttttaaattt gtaaagaatg tctaataaaa tataatctaa 1320ttacatcatg a 1331533207DNAHomo sapiens 53ggcccacaga ggagcacagc tgtgtttggc tgcagggcca agagcgctgt caagaagacc 60cacacgcccc cctccagcag ctgaattcct gcagctcagc agccgccgcc agagcaggac 120gaaccgccaa tcgcaaggca cctctgagaa cttcaggatg cagatgtctc cagccctcac 180ctgcctagtc ctgggcctgg cccttgtctt tggtgaaggg tctgctgtgc accatccccc 240atcctacgtg gcccacctgg cctcagactt cggggtgagg gtgtttcagc aggtggcgca 300ggcctccaag gaccgcaacg tggttttctc accctatggg gtggcctcgg tgttggccat 360gctccagctg acaacaggag gagaaaccca gcagcagatt caagcagcta tgggattcaa 420gattgatgac aagggcatgg cccccgccct ccggcatctg tacaaggagc tcatggggcc 480atggaacaag gatgagatca gcaccacaga cgcgatcttc gtccagcggg atctgaagct 540ggtccagggc ttcatgcccc acttcttcag gctgttccgg agcacggtca agcaagtgga 600cttttcagag gtggagagag ccagattcat catcaatgac tgggtgaaga cacacacaaa 660aggtatgatc agcaacttgc ttgggaaagg agccgtggac cagctgacac ggctggtgct 720ggtgaatgcc ctctacttca acggccagtg gaagactccc ttccccgact ccagcaccca 780ccgccgcctc ttccacaaat cagacggcag cactgtctct gtgcccatga tggctcagac 840caacaagttc aactatactg agttcaccac gcccgatggc cattactacg acatcctgga 900actgccctac cacggggaca ccctcagcat gttcattgct gccccttatg aaaaagaggt 960gcctctctct gccctcacca acattctgag tgcccagctc atcagccact ggaaaggcaa 1020catgaccagg ctgccccgcc tcctggttct gcccaagttc tccctggaga ctgaagtcga 1080cctcaggaag cccctagaga acctgggaat gaccgacatg ttcagacagt ttcaggctga 1140cttcacgagt ctttcagacc aagagcctct ccacgtcgcg caggcgctgc agaaagtgaa 1200gatcgaggtg aacgagagtg gcacggtggc ctcctcatcc acagctgtca tagtctcagc 1260ccgcatggcc cccgaggaga tcatcatgga cagacccttc ctctttgtgg tccggcacaa 1320ccccacagga acagtccttt tcatgggcca agtgatggaa ccctgaccct ggggaaagac 1380gccttcatct gggacaaaac tggagatgca tcgggaaaga agaaactccg aagaaaagaa 1440ttttagtgtt aatgactctt tctgaaggaa gagaagacat ttgccttttg ttaaaagatg 1500gtaaaccaga tctgtctcca agaccttggc ctctccttgg aggaccttta ggtcaaactc 1560cctagtctcc acctgagacc ctgggagaga agtttgaagc acaactccct taaggtctcc 1620aaaccagacg gtgacgcctg cgggaccatc tggggcacct gcttccaccc gtctctctgc 1680ccactcgggt ctgcagacct ggttcccact gaggcccttt gcaggatgga actacggggc 1740ttacaggagc ttttgtgtgc ctggtagaaa ctatttctgt tccagtcaca ttgccatcac 1800tcttgtactg cctgccaccg cggaggaggc tggtgacagg ccaaaggcca gtggaagaaa 1860caccctttca tctcagagtc cactgtggca ctggccaccc ctccccagta caggggtgct 1920gcaggtggca gagtgaatgt cccccatcat gtggcccaac tctcctggcc tggccatctc 1980cctccccaga aacagtgtgc atgggttatt ttggagtgta ggtgacttgt ttactcattg 2040aagcagattt ctgcttcctt ttatttttat aggaatagag gaagaaatgt cagatgcgtg 2100cccagctctt caccccccaa tctcttggtg gggaggggtg tacctaaata tttatcatat 2160ccttgccctt gagtgcttgt tagagagaaa gagaactact aaggaaaata atattattta 2220aactcgctcc tagtgtttct ttgtggtctg tgtcaccgta tctcaggaag tccagccact 2280tgactggcac acacccctcc ggacatccag cgtgacggag cccacactgc caccttgtgg 2340ccgcctgaga ccctcgcgcc ccccgcgccc ctctttttcc ccttgatgga aattgaccat 2400acaatttcat cctccttcag gggatcaaaa ggacggagtg gggggacaga gactcagatg 2460aggacagagt ggtttccaat gtgttcaata gatttaggag cagaaatgca aggggctgca 2520tgacctacca ggacagaact ttccccaatt acagggtgac tcacagccgc attggtgact 2580cacttcaatg tgtcatttcc ggctgctgtg tgtgagcagt ggacacgtga ggggggggtg 2640ggtgagagag acaggcagct cggattcaac taccttagat aatatttctg aaaacctacc 2700agccagaggg tagggcacaa agatggatgt aatgcacttt gggaggccaa ggcgggagga 2760ttgcttgagc ccaggagttc aagaccagcc tgggcaacat accaagaccc ccgtctcttt 2820aaaaatatat atattttaaa tatacttaaa tatatatttc taatatcttt aaatatatat 2880atatatttta aagaccaatt tatgggagaa ttgcacacag atgtgaaatg aatgtaatct 2940aatagaagcc taatcagccc accatgttct ccactgaaaa atcctctttc tttggggttt 3000ttctttcttt cttttttgat tttgcactgg acggtgacgt cagccatgta caggatccac 3060aggggtggtg tcaaatgcta ttgaaattgt gttgaattgt atgctttttc acttttgata 3120aataaacatg taaaaatgtt tcaaaaaaat aataaaataa ataaatacga agaatatgtc 3180aggacagtca aaaaaaaaaa aaaaaaa 3207542414DNAHomo sapiens 54ttttttataa ggccgagcgc gcggcctggc gcagcatacg ccgagccggt ctttgagcgc 60taacgtcttt ctgtctcccc gcggtggtga tgacggtgaa aactgaggct gctaagggca 120ccctcactta ctccaggatg aggggcatgg tggcaattct catcgctttc atgaagcaga 180ggaggatggg tctgaacgac tttattcaga agattgccaa taactcctat gcatgcaaac 240accctgaagt tcagtccatc ttgaagatct cccaacctca ggagcctgag cttatgaatg 300ccaacccttc tcctccacca agtccttctc agcaaatcaa ccttggcccg tcgtccaatc 360ctcatgctaa accatctgac tttcacttct tgaaagtgat cggaaagggc agttttggaa 420aggttcttct agcaagacac aaggcagaag aagtgttcta tgcagtcaaa gttttacaga 480agaaagcaat cctgaaaaag aaagaggaga agcatattat gtcggagcgg aatgttctgt 540tgaagaatgt gaagcaccct ttcctggtgg gccttcactt ctctttccag actgctgaca 600aattgtactt tgtcctagac tacattaatg gtggagagtt gttctaccat ctccagaggg 660aacgctgctt cctggaacca cgggctcgtt tctatgctgc tgaaatagcc agtgccttgg 720gctacctgca ttcactgaac atcgtttata gagacttaaa accagagaat attttgctag 780attcacaggg acacattgtc cttactgact tcggactctg caaggagaac attgaacaca 840acagcacaac atccaccttc tgtggcacgc cggagtatct cgcacctgag gtgcttcata 900agcagcctta tgacaggact gtggactggt ggtgcctggg agctgtcttg tatgagatgc 960tgtatggcct gccgcctttt tatagccgaa acacagctga aatgtacgac aacattctga 1020acaagcctct ccagctgaaa ccaaatatta caaattccgc aagacacctc ctggagggcc 1080tcctgcagaa ggacaggaca aagcggctcg gggccaagga tgacttcatg gagattaaga 1140gtcatgtctt cttctcctta attaactggg atgatctcat taataagaag attactcccc 1200cttttaaccc aaatgtgagt gggcccaacg acctacggca ctttgacccc gagtttaccg 1260aagagcctgt ccccaactcc attggcaagt cccctgacag cgtcctcgtc acagccagcg 1320tcaaggaagc tgccgaggct ttcctaggct tttcctatgc gcctcccacg gactctttcc 1380tctgaaccct gttagggctt ggttttaaag gattttatgt gtgtttccga atgttttagt 1440tagccttttg gtggagccgc cagctgacag gacatcttac aagagaattt gcacatctct 1500ggaagcttag caatcttatt gcacactgtt cgctggaagc tttttgaaga gcacattctc 1560ctcagtgagc tcatgaggtt ttcattttta ttcttccttc caacgtggtg ctatctctga 1620aacgagcgtt agagtgccgc cttagacgga ggcaggagtt tcgttagaaa gcggacgctg 1680ttctaaaaaa ggtctcctgc agatctgtct gggctgtgat gacgaatatt atgaaatgtg 1740ccttttctga agagattgtg ttagctccaa agcttttcct atcgcagtgt ttcagttctt 1800tattttccct tgtggatatg ctgtgtgaac cgtcgtgtga gtgtggtatg cctgatcaca 1860gatggatttt gttataagca tcaatgtgac acttgcagga cactacaacg tgggacattg 1920tttgtttctt ccatatttgg aagataaatt tatgtgtaga cttttttgta agatacggtt 1980aataactaaa atttattgaa atggtcttgc aatgactcgt attcagatgc ttaaagaaag 2040cattgctgct acaaatattt ctatttttag aaagggtttt tatggaccaa tgccccagtt 2100gtcagtcaga gccgttggtg tttttcattg tttaaaatgt cacctgtaaa atgggcatta 2160tttatgtttt tttttttgca ttcctgataa ttgtatgtat tgtataaaga acgtctgtac 2220attgggttat aacactagta tatttaaact tacaggctta tttgtaatgt aaaccaccat 2280tttaatgtac tgtaattaac atggttataa tacgtacaat ccttccctca tcccatcaca 2340caactttttt tgtgtgtgat aaactgattt tggtttgcaa taaaaccttg aaaaatattt 2400acatataaaa aaaa 2414557202DNAHomo sapiens 55gatgtgtgtg gggttcggag ccgcgccggc acagccgaag ggagcgggcg agcggcgacg 60gcggcggcgg cgggcacaga ttaattaaaa gaagaatgaa ctataatcct tgaagataac 120tgggcaattt tttaagtcgg aggctgttct tactggtgtg aggatttaca cacgtcttca 180gtttttcagc acagaccagc agaccatcat ttttagagga aatactccct ctgccctcct 240ttttggtttc cttggtggta aagattaaat ttggttgcat cattttgact tgtgtttgag 300tctagatttt atggcacaag gaatggcata aacttttcat gtgttttggt taaaacaaac 360cagaccattg cattgaccct ggacatcttt aattgagaaa ttggtaactt tattttaata 420tgtatatctg aagaattcaa gaaaacaaag gcatcctcag aggtgtgcct cttttcttta 480ttattagagg caaaacgaac aattttatag gatttgtagt gaaattatac cagattataa 540ggagaaccaa aactaagtcg caaaatttat taatttaagg ggctctcgct ttgaaagttt 600gagagtaagt tacgataggc atttgtatcc attcattact ttcctctttt caaataagca 660actaaataga aatgctaatc tcagacttaa ttatttaaca gaagagtgta ccatggaaaa 720cctccagaca aatttctcct tggttcaggg ctcaactaaa aaactgaatg ggatgggaga 780tgatggcagc cccccagcga aaaaaatgat aacggacatt catgcaaatg gaaaaacgat 840aaacaaggtg ccaacagtta agaaggaaca cttggatgac tatggagaag caccagtgga 900aactgatgga gagcatgtta agcgaacctg tacttctgtt cctgaaactt tgcatttaaa 960tcccagtttg aaacacacat tggcacaatt ccatttaagt agtcagagct cgctgggtgg 1020accagcagca ttttctgctc ggcattccca agaaagcatg tcgcctactg tatttctgcc 1080tcttccatca cctcaggttc ttcctggccc attgctcatc ccttcagata gctccacaga 1140actcactcag actgtgttgg aaggggaatc tatttcttgt tttcaagttg gaggagaaaa 1200gagactctgt ttgccccaag tcttaaattc tgttctccga gaatttacac tccagcaaat 1260aaatacagtg tgtgatgaac tgtacatata ttgttcaagg tgtacttcag accagcttca 1320tatcttaaag gtactgggca tacttccatt caatgcccca tcctgtgggc tgattacatt 1380aactgatgca caaagattat gtaatgcttt attgcggcca cgaacttttc ctcaaaatgg 1440tagcgtactt cctgctaaaa gctcattggc ccagttaaag gaaactggca gtgcctttga 1500agtggagcat gaatgcctag gcaaatgtca gggtttattt gcaccccagt tttatgttca 1560gcctgatgct ccgtgtattc aatgtctgga gtgttgtgga atgtttgcac cccagacgtt 1620tgtgatgcat tctcacagat cacctgacaa aagaacttgc cactggggct ttgaatcagc 1680taaatggcat tgctatcttc atgtgaacca aaaatactta ggaacacctg aagaaaagaa 1740actgaagata attttagaag aaatgaagga gaagtttagc atgagaagtg gaaagagaaa 1800tcaatccaag acagatgcac catcaggaat ggaattacag tcatggtatc ctgttataaa 1860gcaggaaggt gaccatgttt ctcagacaca ttcattttta caccccagct actacttata 1920catgtgtgat aaagtggttg ccccaaatgt gtcacttact tctgctgtat cccagtctaa 1980agagctcaca aagacagagg caagtaagtc catatcaaga cagtcagaga aggctcacag 2040tagtggtaaa cttcaaaaaa cagtgtctta tccagatgtc tcacttgagg aacaggagaa 2100aatggattta aaaacaagta gagaattatg tagccgttta gatgcatcaa tctcaaataa 2160ttctacaagt aaaaggaaat ctgagtctgc cacttgcaac ttagtcagag acataaacaa 2220agtgggaatt ggccttgttg ctgccgcttc atctccgctt cttgtgaaag atgtcatttg 2280tgaggatgat aagggaaaaa tcatggaaga agtaatgaga acttatttaa aacaacagga 2340aaaactaaac ttgattttgc aaaagaagca acaacttcag atggaagtaa aaatgttgag 2400tagttcaaaa tctatgaagg aactcactga agaacagcag aatttacaga aagagcttga 2460atctttgcag aatgaacatg ctcaaagaat ggaagaattt tatgttgaac agaaagactt 2520agagaaaaaa ttggagcaga taatgaagca aaaatgtacc tgtgactcaa atttagaaaa 2580agacaaagag gctgaatatg caggacagtt ggcagaactg aggcagagat tggaccatgc 2640tgaggccgat aggcaagaac tccaagatga actcagacag gaacgggaag caagacagaa 2700gttagagatg atgataaaag agctaaagct gcaaattctg aaatcatcaa agactgctaa 2760agaatagaaa ctgttaaaga gattcatctg tgtattactg acaaggtttt ttttgtttgt 2820tgcttgcttt ggtaattgaa ttctgaagaa tttatctgca tgacgataac taggcattct 2880atccatttgt agatcagaga aagtgaagag attatatatt agtacttaaa tttttacatt 2940ttccaaatga atgaaaatgt atgtttcttt gtactttttt aaaaaaatca gcttagtaac 3000aatactatat ggtttcaact agtaggtaat ctgcttatat ttctaatgca aacttaacaa 3060ttgtgtactt tttaaaagct gcaatatgtg ttggaaaata gctgtggtca attttgttat 3120ccatatttca gactcaattt tagatacaat ggtggcttta tattttaagt atatagagct 3180actcaaggag ttgaatctcc ccttttctca ttaacacaat ttttctaagt tgatatggtg 3240tactcattaa catacaccaa atttactttt actttgttca gattgtggaa tgaatttcca 3300ccagttctct tctttttaat gtgtacccta ggaggaattt tactgaggtt atagcatacc 3360ccatgagcac agtggggaag aagaatgtgt tgttatgtgc tgctgctaaa cagaagcagc 3420agttgtaatt tgtttttcag tttaaatgtg gttatagtta gatttttttt taagcagcaa 3480cttttcaaaa ataaaatgtg ataatttctg aacttttgtt tgtgttgtta atagtggtgt 3540gaaaatatta acgttcttga gaaaaactga taccactgtt gtgtatcagt ttctatacaa 3600tccataatcc tcctgtacag tttttacatg tagttatgag tcttactaaa atttatataa 3660tggacttgtt ttcctttaag ttgtaaaatg ttaaacacct tgaaggttat tttggacttc 3720tgtatgttta aatgttgtct taccaaaatt tgcacgaatg gaccattttc atttactact 3780taatatcaaa atcaggaatt tacagtcaac tgatagtaca tgataggtgc atataggaca 3840gtttagttac ctgctactaa aagattttta gataagtttt agaagataaa ggaattccat 3900agtttcagga gggacaacat cttctgcact ttttttttgc acagaaaagt ctgtcattct 3960ctaatggcaa atttcatatt tgttaattct tggctcaaaa tatattaggt aaaattctta 4020gatctgtttt taaagggagt ttcctgaaac tatcattaat tgacattatt accccatgga 4080ttttatggga taataaatgt ttttcatgtt ctcttataag atactatgta tgaaattact 4140tcagagagct atatttattt taaaataaat tagctagggt taaggttata ttctatttcc 4200agcatagaag gtagataatc taatggtgta gaaagaatca ctaggttgtc atttaaccag 4260ttattttcat attttgctta atagtacata tccaaaaaga attttgtact tccccaaatg 4320taatttattt actaaattga gtataaccta aatgtgtgtt ttctattttc catttaaatt 4380ttgctatatt aagactaatt taattcgttg agtcttggaa tcttctcaag gaggaacaaa 4440tattaaaatg acatgtagaa acaaattttt tttttttttt tttttttttt ttttttgaga 4500cagagtctcg ctgtctccca ggctggagtt cagtggtgca atctcggctc actgcaagct 4560ctgcctcctg ggttcaagcc attctcctgc ctcagcctcc cgagtagctg ggactacagg 4620cacccaccac cactcccggc taatttttag aaacaaatat ttaaaatgac atattctccc 4680aatacaatct atttagatct ggagaaggaa aaatcagata tttatgatat agttttattt 4740taattttgaa ttatttgtgt cacagctcag ctttttggaa gacaaactca aacacctata 4800atttcattta tatttctaat tcacttggaa cctttctgct ttatgttacc tagaaaatga 4860taatttgttt aacccaaaac ttctaaaata aattgcttaa tccttgaaat atgttattgg 4920aaaattttaa gcagtgctta aacaccatta aattattatg aacttgtaat tcagaattga 4980gtaaagaaat attttttcta gtccttcata tattgaaaac ttgccacatg acattgtatc 5040gtcttcattt tccagaagat gcgttggtgt gccataggtt tctaacttcc ttgaaaatag 5100ttttttaagt caattgtaaa tatacgtatt attgttaaaa gtaactttaa actgcaacac 5160atagcttcaa aacaatatag agattttgta ataccttata agtggagttg gctaaaatac 5220cttatccata taaaacttat tctattcttt gcatgcttat tttgtgtgtt ggttgctagc 5280ttaaagtttg atttgttgtt actctttgtg tgccaaattc actaggcaag cggatttttc 5340ctcagacttc aaaaaataat tcttttaaga aaaaatgtaa aaatgtttat tctaaaaagc 5400tgcattaaag ggacaaccta taaaaagttt tgctagctca tctttagaag gaagaaagaa 5460tattagcttg ggtgatgttt aatttgggtg gcgatagttt ctgtaggcta aactttatga 5520gaaaagtgta cctactctat aaaggtaata aatgtaaaac ctcttgctgt tattgaggaa 5580gctcttcaac taccctaaat ttcacaaatg taacttataa cactatgaaa agatttgacc 5640aacaatttac gtttgctgtg tgctttagtt tttgtttaag catattcttt tgcttgaatt 5700tctgtgttca tgagagttag ggtgttttat gcttcttgaa ctaattttat aacatattta 5760atatattacc agttaagata taaaatcatt tgtacatagc gaattgtaaa gcagctatta 5820aagtaggtga aataaagtat atatttgccg gttatccata tcttttagaa gtcctgacag 5880aacaaccagt ttatttgcac ataggtagct tctgtttgaa ggaaggtaaa gttataagga 5940aactcaaata ctataagatg tgtcaaggta tttctccaga attaattgca aagctagtgc 6000tgaaggattt taatcagctt ctaaaatttt cttctcaata aggcatatgt tttgattact 6060tagggaagat tcctcatttt tatttgccct ttatgcattt

aatccacatg ataggacatt 6120aaaaattaat ataaagaaaa atcgtgctca tactgtacat ctgtttctgt gcttggaact 6180acttgttaat agtttttatc gaagctgtca gcaataaggg acataaaact gctgtattat 6240acattgtgga attgaataaa cagcctaatt ttttttttct agtatagggt acttaagcat 6300ttccactttt ggaagaaaag tgtattagta ttttatattg catttcattt aaaaggacag 6360tttttttttt ttttttgtaa atccattcat tgaaatggtt tctaaactgt ataatgtaat 6420ttggagccta tttagtaata gaattaaatg tcctatgtag tgctacaatt tttgaattag 6480aaagtgatca aatgtaagaa aaaaatttaa aaattcagcc cagaaaacaa aatagtgtat 6540taaattagtt taatgtaaaa ggaatttata agattttttt cctcaatata gatacctcac 6600ttgaaaagaa agcacagcat acttaaagta gttctagtaa acatgtccta gaaaacagtt 6660gctaaatgta ggacatcttt tgaggaatta gtttatgaga aataaaattt tacttgtttt 6720tactatcctg ttagaagtat ttgtttatcc tgataatttt aagccaacat agtagtctta 6780aattactttt gaatttctaa tctgtgaagg cagtaaatga aatatctgtt ctgcaactgt 6840tgaaacaaat aattggctac attgaccata attaaagtta aaattttgcc aatgatgtac 6900agttttatgg ttaaagttgc tgtggttggt tgcattacat gacacagaaa actgtcctct 6960acctcacgtg aaataaatat tttatatggt tttactaaaa ataagactca tgtatctggt 7020cacctagttt acaaattttg aattatattt attgaaacat gacatactgt gctctgagct 7080tatacctcaa ttgtattttg tgctgttttc cattttcatg ccttgtaaat aacttgtata 7140gattgtggat caaatactaa ataaaaactt ttaatgccaa ttaaatttga ttcaagttaa 7200aa 7202561351DNAHomo sapiens 56agctccggct ccccctatat aaatcggcca tttgcttcgc tccgccccgc agcgccggag 60tcaaagccgg ttcccggccc agtcccgtcc tgcagcagtc tgcctcctct ttcaacatga 120cagatgccgc tgtgtccttc gccaaggact tcctggcagg tggagtggcc gcagccatct 180ccaagacggc ggtagcgccc atcgagcggg tcaagctgct gctgcaggtg cagcatgcca 240gcaagcagat cactgcagat aagcaataca aaggcattat agactgcgtg gtccgtattc 300ccaaggagca gggagttctg tccttctggc gcggtaacct ggccaatgtc atcagatact 360tccccaccca ggctcttaac ttcgccttca aagataaata caagcagatc ttcctgggtg 420gtgtggacaa gagaacccag ttttggctct actttgcagg gaatctggca tcgggtggtg 480ccgcaggggc cacatccctg tgttttgtgt accctcttga ttttgcccgt acccgtctag 540cagctgatgt gggtaaagct ggagctgaaa gggaattccg aggcctcggt gactgcctgg 600ttaagatcta caaatctgat gggattaagg gcctgtacca aggctttaac gtgtctgtgc 660agggtattat catctaccga gccgcctact tcggtatcta tgacactgca aagggaatgc 720ttccggatcc caagaacact cacatcgtca tcagctggat gatcgcacag actgtcactg 780ctgttgccgg gttgacttcc tatccatttg acactgttcg ccgccgcatg atgatgcagt 840cagggcgcaa aggaactgac atcatgtaca caggcacgct tgactgctgg cggaagattg 900ctcgtgatga aggaggcaaa gcttttttca agggtgcatg gtccaatgtt ctcagaggca 960tgggtggtgc ttttgtgctt gtcttgtatg atgaaatcaa gaagtacaca taagttattt 1020cctaggattt ttccccctgt gaacaggcat gttgtattat ataacatatc ttgagcattc 1080ttgacagact cctggctgtc agtttctcag tggcaactat ttactggttg aaaatgggaa 1140gcaataatat tcatctgacc agttttctct taaagccatt tccatgatga tgatgatggg 1200actcaattgt attttttatt tcagtcactc ctgataaata acaaatttgg agaaataaaa 1260atatctaaaa taaattttgt ctgcagtata ttttcatata aaaatgcata tttgagtgct 1320acattcgaat aaatactacc tttttagtga a 1351578789DNAHomo sapiens 57atgctcagtg gcttctcgac aagttggcag caacaacacg gccctggtcg tcgtcgccgc 60tgcggtaacg gagcggtttg ggtggcggag cctgcgttcg cgccttcccg ctctcctcgg 120gaggcccttc ctgctctccc ctaggctccg cggccgccca gggggtggga gcgggtgagg 180ggagccaggc gcccagcgag agaggccccc cgccgcaggg cggcccggga gctcgaggcg 240gtccggcccg cgcgggcagc ggcgcggcgc tgaggagggg cggcctggcc gggacgcctc 300ggggcggggg ccgaggagct ctccgggccg ccggggaaag ctacgggccc ggtgcgtccg 360cggaccagca gcgcgggaga gcggactccc ctcgccaccg cccgagccca ggttatcctg 420aatacatgtc taacaatttt ccttgcaacg ttagctgttg tttttcactg tttccaaagg 480atcaaaattg cttcagaaat tggagacata tttgatttaa aaggaaaaac ttgaacaaat 540ggacaatatg tctattacga atacaccaac aagtaatgat gcctgtctga gcattgtgca 600tagtttgatg tgccatagac aaggtggaga gagtgaaaca tttgcaaaaa gagcaattga 660aagtttggta aagaagctga aggagaaaaa agatgaattg gattctttaa taacagctat 720aactacaaat ggagctcatc ctagtaaatg tgttaccata cagagaacat tggatgggag 780gcttcaggtg gctggtcgga aaggatttcc tcatgtgatc tatgcccgtc tctggaggtg 840gcctgatctt cacaaaaatg aactaaaaca tgttaaatat tgtcagtatg cgtttgactt 900aaaatgtgat agtgtctgtg tgaatccata tcactacgaa cgagttgtat cacctggaat 960tgatctctca ggattaacac tgcagagtaa tgctccatca agtatgatgg tgaaggatga 1020atatgtgcat gactttgagg gacagccatc gttgtccact gaaggacatt caattcaaac 1080catccagcat ccaccaagta atcgtgcatc gacagagaca tacagcaccc cagctctgtt 1140agccccatct gagtctaatg ctaccagcac tgccaacttt cccaacattc ctgtggcttc 1200cacaagtcag cctgccagta tactgggggg cagccatagt gaaggactgt tgcagatagc 1260atcagggcct cagccaggac agcagcagaa tggatttact ggtcagccag ctacttacca 1320tcataacagc actaccacct ggactggaag taggactgca ccatacacac ctaatttgcc 1380tcaccaccaa aacggccatc ttcagcacca cccgcctatg ccgccccatc ccggacatta 1440ctggcctgtt cacaatgagc ttgcattcca gcctcccatt tccaatcatc ctgctcctga 1500gtattggtgt tccattgctt actttgaaat ggatgttcag gtaggagaga catttaaggt 1560tccttcaagc tgccctattg ttactgttga tggatacgtg gacccttctg gaggagatcg 1620cttttgtttg ggtcaactct ccaatgtcca caggacagaa gccattgaga gagcaaggtt 1680gcacataggc aaaggtgtgc agttggaatg taaaggtgaa ggtgatgttt gggtcaggtg 1740ccttagtgac cacgcggtct ttgtacagag ttactactta gacagagaag ctgggcgtgc 1800acctggagat gctgttcata agatctaccc aagtgcatat ataaaggtct ttgatttgcg 1860tcagtgtcat cgacagatgc agcagcaggc ggctactgca caagctgcag cagctgccca 1920ggcagcagcc gtggcaggaa acatccctgg cccaggatca gtaggtggaa tagctccagc 1980tatcagtctg tcagctgctg ctggaattgg tgttgatgac cttcgtcgct tatgcatact 2040caggatgagt tttgtgaaag gctggggacc ggattaccca agacagagca tcaaagaaac 2100accttgctgg attgaaattc acttacaccg ggccctccag ctcctagacg aagtacttca 2160taccatgccg attgcagacc cacaaccttt agactgaggt cttttaccgt tggggccctt 2220aaccttatca ggatggtgga ctacaaaata caatcctgtt tataatctga agatatattt 2280cacttttgtt ctgctttatc ttttcataaa gggttgaaaa tgtgtttgct gccttgctcc 2340tagcagacag aaactggatt aaaacaattt tttttttcct cttcagaact tgtcaggcat 2400ggctcagagc ttgaagatta ggagaaacac attcttatta attcttcacc tgttatgtat 2460gaaggaatca ttccagtgct agaaaattta gccctttaaa acgtcttaga gccttttatc 2520tgcagaacat cgatatgtat atcattctac agaataatcc agtattgctg attttaaagg 2580cagagaagtt ctcaaagtta attcacctat gttattttgt gtacaagttg ttattgttga 2640acatacttca aaaataatgt gccatgtggg tgagttaatt ttaccaagag taactttact 2700ctgtgtttaa aaagtaagtt aataatgtat tgtaatcttt catccaaaat attttttgca 2760agttatatta gtgaagatgg tttcaattca gattgtcttg caacttcagt tttatttttg 2820ccaaggcaaa aaactcttaa tctgtgtgta tattgagaat cccttaaaat taccagacaa 2880aaaaatttaa aattacgttt gttattccta gtggatgact gttgatgaag tatacttttc 2940ccctgttaaa cagtagttgt attcttctgt atttctaggc acaaggttgg ttgctaagaa 3000gcctataaga ggaatttctt ttccttcatt catagggaaa ggttttgtat tttttaaaac 3060actaaaagca gcgtcactct acctaatgtc tcactgttct gcaaaggtgg caatgcttaa 3120actaaataat gaataaactg aatattttgg aaactgctaa attctatgtt aaatactgtg 3180cagaataatg gaaacattac agttcataat aggtagtttg gatatttttg tacttgattt 3240gatgtgactt tttttggtat aatgtttaaa tcatgtatgt tatgatattg tttaaaattc 3300agtttttgta tcttggggca agactgcaaa cttttttata tcttttggtt attctaagcc 3360ctttgccatc aatgatcata tcaattggca gtgactttgt atagagaatt taagtagaaa 3420agttgcagat gtattgactg taccacagac acaatatgta tgctttttac ctagctggta 3480gcataaataa aactgaatct caacatacaa agttgaattc taggtttgat ttttaagatt 3540ttttttttct tttgcacttt tgagtccaat ctcagtgatg aggtaccttc tactaaatga 3600caggcaacag ccagttctat tgggcagctt tgtttttttc cctcacactc taccgggact 3660tccccatgga cattgtgtat catgtgtaga gttggttttt ttttttttta atttttattt 3720tactatagca gaaatagacc tgattatcta caagatgata aatagattgt ctacaggata 3780aatagtatga aataaaatca aggattatct ttcagatgtg tttacttttg cctggagaac 3840ttttagctat agaaacactt gtgtgatgat agtcctcctt atatcacctg gaatgaacac 3900agcttctact gccttgctca gaaggtcttt taaatagacc atcctagaaa ccactgagtt 3960tgcttatttc tgtgatttaa acatagatct tgatccaagc tacatgactt ttgtctttaa 4020ataacttatc taccacctca tttgtactct tgattactta caaattcttt cagtaaacac 4080ctaattttct tctgtaaaag tttggtgatt taagttttat tggcagtttt ataaaaagac 4140atcttctcta gaaattgcta actttaggtc cattttactg tgaatgagga ataggagtga 4200gttttagaat aacagatttt taaaaatcca gatgatttga ttaaaacctt aatcatacat 4260tgacataatt cattgcttct tttttttgag atatggagtc ttgctgtgtt gcccaggcag 4320gagtgcagtg gtatgatctc agctcactgc aacctctgcc tcccgggttc aactgattct 4380cctgcctcag cctccctggt agctaggatt acaggtgccc gccaccatgc ctggctaact 4440tttgtagttt tagtagagac ggggttttgc ctgttggcca ggctggtctt gaactcctga 4500cctcaagtga tccatccacc ttggcctccc aaagtgctgg gattacgggc gtgagccact 4560gtccctggcc tcattgttcc cttttctact ttaaggaaag ttttcatgtt taatcatctg 4620gggaaagtat gtgaaaaata tttgttaaga agtatctctt tggagccaag ccacctgtct 4680tggtttcttt ctactaagag ccataaagta tagaaatact tctagttgtt aagtgcttat 4740atttgtacct agatttagtc acacgctttt gagaaaacat ctagtatgtt atgatcagct 4800attcctgaga gcttggttgt taatctatat ttctatttct tagtggtagt catctttgat 4860gaataagact aaagattctc acaggtttaa aattttatgt ctactttaag ggtaaaatta 4920tgaggttatg gttctgggtg ggttttctct agctaattca tatctcaaag agtctcaaaa 4980tgttgaattt cagtgcaagc tgaatgagag atgagccatg tacacccacc gtaagacctc 5040attccatgtt tgtccagtgc ctttcagtgc attatcaaag ggaatccttc atggtgttgc 5100ctttattttc cggggagtag atcgtgggat atagtctatc tcatttttaa tagtttaccg 5160cccctggtat acaaagataa tgacaataaa tcactgccat ataaccttgc tttttccaga 5220aacatggctg ttttgtattg ctgtaaccac taaataggtt gcctatacca ttcctcctgt 5280gaacagtgca gatttacagg ttgcatggtc tggcttaagg agagccatac ttgagacatg 5340tgagtaaact gaactcatat tagctgtgct gcatttcaga cttaaaatcc atttttgtgg 5400ggcagggtgt ggtgtgtaaa ggggggtgtt tgtaatacaa gttgaaggca aaataaaatg 5460tcctgtctcc cagatgatat acatcttatt atttttaaag tttattgcta attgtaggaa 5520ggtgagttgc aggtatcttt gactatggtc atctggggaa ggaaaatttt acattttact 5580attaatgctc cttaagtgtc tatggaggtt aaagaataaa atggtaaatg tttctgtgcc 5640tggtttgatg gtaactggtt aatagttact caccatttta tgcagagtca cattagttca 5700caccctttct gagagccttt tgggagaagc agttttattc tctgagtgga acagagttct 5760ttttgttgat aatttctagt ttgctccctt cgttattgcc aactttactg gcattttatt 5820taatgatagc agattgggaa aatggcaaat ttaggttacg gaggtaaatg agtatatgaa 5880agcaattacc tctaaagcca gttaacaatt attttgtagg tggggtacac tcagcttaaa 5940gtaatgcatt tttttttccc gtaaaggcag aatccatctt gttgcagata gctatctaaa 6000taatctcata tcctcttttg caaagactac agagaatagg ctatgacaat cttgttcaag 6060cctttccatt tttttccctg ataactaagt aatttctttg aacataccaa gaagtatgta 6120aaaagtccat ggccttattc atccacaaag tggcatccta ggcccagcct tatccctagc 6180agttgtccca gtgctgctag gttgcttatc ttgtttatct ggaatcactg tggagtgaaa 6240ttttccacat catccagaat tgccttattt aagaagtaaa acgttttaat ttttagcctt 6300tttttggtgg agttatttaa tatgtatatc agaggatata ctagatggta acatttcttt 6360ctgtgcttgg ctatctttgt ggacttcagg ggcttctaaa acagacagga ctgtgttgcc 6420tttactaaat ggtctgagac agctatggtt ttgaattttt agtttttttt ttttaaccca 6480cttcccctcc tggtctcttc cctctctgat aattaccatt catatgtgag tgttagtgtg 6540cctcctttta gcattttctt cttctctttc tgattcttca tttctgactg cctaggcaag 6600gaaaccagat aaccaaactt actagaacgt tctttaaaac acaagtacaa actctgggac 6660aggacccaag acactttcct gtgaagtgct gaaaaagacc tcattgtatt ggcatttgat 6720atcagtttga tgtagcttag agtgcttcct gattcttgct gagtttcagg tagttgagat 6780agagagaagt gagtcatatt catattttcc cccttagaat aatattttga aaggtttcat 6840tgcttccact tgaatgctgc tcttacaaaa actggggtta caagggttac taaattagca 6900tcagtagcca gaggcaatac cgttgtctgg aggacaccag caaacaacac acaacaaagc 6960aaaacaaacc ttgggaaact aaggccattt gttttgtttt ggtgtcccct ttgaagccct 7020gccttctggc cttactcctg tacagatatt tttgacctat aggtgccttt atgagaattg 7080agggtctgac atcctgcccc aaggagtagc taaagtaatt gctagtgttt tcagggattt 7140taacatcaga ctggaatgaa tgaatgaaac tttttgtcct ttttttttct gttttttttt 7200ttctaatgta gtaaggacta aggaaaacct ttggtgaaga caatcatttc tctctgttga 7260tgtggatact tttcacaccg tttatttaaa tgctttctca ataggtccag agccagtgtt 7320cttgttcaac ctgaaagtaa tggctctggg ttgggccaga cagttgcact ctctagtttg 7380ccctctgcca caaatttgat gtgtgacctt tgggcaagtc atttatcttc tctgggcctt 7440agttgcctca tctgtaaaat gagggagttg gagtagatta attattccag ctctgaaatt 7500ctaagtgacc ttggctacct tgcagcagtt ttggatttct tccttatctt tgttctgctg 7560tttgaggggg ctttttactt atttccatgt tattcaaagg agactaggct tgatatttta 7620ttactgttct tttatggaca aaaggttaca tagtatgccc ttaagactta attttaacca 7680aaggcctagc accaccttag gggctgcaat aaacacttaa cgcgcgtgcg cacgcgcgcg 7740cgcacacaca cacacacaca cacacacaca cacaggtcag agtttaaggc tttcgagtca 7800tgacattcta gcttttgaat tgcgtgcaca cacacacgca cgcacacact ctggtcagag 7860tttattaagg ctttcgagtc atgacattat agcttttgag ttggtgtgtg tgacaccacc 7920ctcctaagtg gtgtgtgctt gtaatttttt ttttcagtga aaatggattg aaaacctgtt 7980gttaatgctt agtgatatta tgctcaaaac aaggaaattc ccttgaaccg tgtcaattaa 8040actggtttat atgactcaag aaaacaatac cagtagatga ttattaactt tattcttggc 8100tctttttagg tccattttga ttaagtgact tttggctgga tcattcagag ctctcttcta 8160gcctaccctt ggatgagtac aattaatgaa attcatattt tcaaggacct gggagccttc 8220cttggggctg ggttgagggt ggggggttgg ggagtcctgg tagaggccag ctttgtggta 8280gctggagagg aagggatgaa accagctgct gttgcaaagg ctgcttgtca ttgatagaag 8340gactcacggg cttggattga ttaagactaa acatggagtt ggcaaacttt cttcaagtat 8400tgagttctgt tcaatgcatt ggacatgtga tttaagggaa aagtgtgaat gcttatagat 8460gatgaaaacc tggtgggctg cagagcccag tttagaagaa gtgagttggg ggttggggac 8520agatttggtg gtggtatttc ccaactgttt cctcccctaa attcagagga atgcagctat 8580gccagaagcc agagaagagc cactcgtagc ttctgctttg gggacaactg gtcagttgaa 8640agtcccagga gttcctttgt ggctttctgt atacttttgc ctggttaaag tctgtggcta 8700aaaaatagtc gaacctttct tgagaactct gtaacaaagt atgtttttga ttaaaagaga 8760aagccaacta aaaaaaaaaa aaaaaaaaa 8789587014DNAHomo sapiens 58atccgggtcc tgggcgagcg ggcgccgtgc gcgtgtcccg cggccgagct gctaataaag 60ttgcagcgag gagaagcgca gcgacggcgt cgggagagcg cgcctagccg gctcgcgaaa 120aggaagctgt tgaagttatt gaagtacctg ttgctatatt ctaagaaatt aaaatgtcca 180gaaatctgcc tctgacttga cccaatgaaa gaagcatatg gcacttgtga agataaatgt 240tactcctccc tttttaattg gaacttctgc ttaggacctg tgtatgacgt ttcacctgtg 300atctgttctt tcggtagcca ctgactttga gttacaggaa ggtctccgaa gatttgtgtc 360aaatgacgtc aatggccagc ttgttttctt ttactagtcc agcagtaaag cgattgttgg 420gctggaaaca aggtgatgag gaggagaaat gggcagaaaa ggcagttgat gctttggtga 480agaaactaaa aaagaaaaag ggtgccatgg aggaactgga gaaagccttg agcagtccag 540gacagccgag taaatgtgtc actattccca gatctttaga tggacgcctg caggtttctc 600acagaaaagg cttaccccat gttatatatt gtcgtgtttg gcgctggccg gatttgcaga 660gtcatcatga gctaaagccg ttggatattt gtgaatttcc ttttggatct aagcaaaaag 720aagtttgtat caacccatac cactataaga gagtggagag tccagtctta cctccagtat 780tagtgcctcg tcataatgaa ttcaatccac aacacagcct tctggttcag tttaggaacc 840tgagccacaa tgaaccacac atgccacaaa atgccacgtt tccagattct ttccaccagc 900ccaacaacac tccttttccc ttatctccaa acagccctta tcccccttct cctgctagca 960gcacatatcc caactcccca gcaagttctg gaccaggaag tccatttcag ctcccagctg 1020atacgcctcc tcctgcctat atgccacctg atgatcagat gggtcaagat aattcccagc 1080ctatggatac aagcaataat atgattcctc agattatgcc cagtatatcc agcagggatg 1140ttcagcctgt tgcctatgaa gagcctaaac attggtgttc aatagtctac tatgaattaa 1200acaatcgtgt tggagaagct tttcatgcat cttctactag tgtgttagta gatggattca 1260cagatccttc aaataacaaa agtagattct gcttgggttt gttgtcaaat gttaatcgta 1320attcgacaat tgaaaacact aggcgacata ttggaaaagg tgttcatctg tactatgttg 1380gtggagaggt gtatgcggaa tgcctcagtg acagcagcat atttgtacag agtaggaact 1440gcaactttca tcatggcttt catcccacca ctgtctgtaa gattcccagc agctgcagcc 1500tcaaaatttt taacaatcag gagtttgctc agcttctggc tcaatctgtc aaccatgggt 1560ttgaggcagt atatgagctc accaaaatgt gtaccattcg gatgagtttt gtcaagggtt 1620ggggagcaga atatcaccgg caggatgtaa ccagcacccc atgttggatt gagattcatc 1680ttcatgggcc tcttcagtgg ctggataaag tccttactca gatgggctcc cctctgaacc 1740ccatatcttc tgtttcataa tgcagaagta ttcttttcaa ttatattgtt agtggacttg 1800ttttaatttt agagaaactt tgagtacaga tactgtgagc ttacattgaa aacagatatt 1860acagcttatt tttttctaca taattgtgac caatacattt gtattttgtg atgaatctac 1920atttgtttgt attcatgttc atgtgattaa ctcttagaag tgttgtaaaa gatgcagagt 1980aagtattatg ccccagttca gaaatttggc attgatctta aactggaaca tgcttttact 2040ttattgccct aacaattttt tattaaattt atttgaaaat gcatcacatg atgaaaaatt 2100atagtagctt ataagagggc atatacagtg aagagtaagt tttccctcct actctcgatc 2160ttccagaagc tgtactttta ccagtttctt tgtcccacca acttaaaaaa aaaaagtaca 2220attcattgtt ttgcaaaagt gtatggtagg ggcttaaaag aaactataaa gttttatttg 2280aatgaacact atgcactgct gtaactggta gtgttcagta aaagcaaaat gatagttttc 2340tagatgacat aaaatttaca tttaatacag ataagtgttc ttcagtgtaa tgtgacttca 2400tgctatatat cttttgtaag acatttcctt ttttaaaaaa atttttgcaa ataactgatc 2460tcaagtatat gtcatttact caaaatctgt cataagcatt actttatagc tagtgacagt 2520gcatgcacag ccttgttcaa ctatgtttgc tgcttttgga caatgttgca agaactctat 2580ttttgacatg cattaatctt ttattttgca cttttatggg tgacagtttt tagcataacc 2640tttgataaaa tacactcaag tgacttggac ttagatgctt atccttacgt ccttggtacc 2700ttttttgtat taacaaacac tgcaatttat agattacatt tgtaggaagt tatgcttttt 2760tctggttttt gttttacttt caacctaggt tataagactg ttattctata gctccaactt 2820aaggtgcctt tttaattccc tacagtttta tgggtgttat cagtgctgga gaatcatgta 2880gttaatccca ttgctcttac aagtgtcagc ttacttgtat cagcctccct acgcaaggac 2940ctatgcactg gagccgtagg aggctcttca gttgggcccc aaggataagg ctactgattt 3000gatactaaat gaatcagcag tggatgtagg gatagctgat tttaaaacac tcggctgggc 3060acagtggctc acacctgtaa tcccagcact ttgggaggct gaggcaggca gatcatgatg 3120tcaggagttt gagaccagcc tggccaatat ggtgaaaccc tgtctctaca aaaaatacaa 3180aaattagctg ggcatggtgg tgcgtgcctg aagtcccagc tactcgggaa gctgaggcag 3240aagaatcact tgaacctggg aggcggaggt tgtggtgagc cgagatcgca ccactgcact 3300ccagcctggg cgacagagcg agactctgcc tcaaaaaaca aaacaaaaca aaacactcac 3360ccatcaacga atatagactc ttctctcatt tatcgatgat cctctttttc cattttttaa 3420gtacttatgt ggaagctagt ctcccaaaac acaatcttta gagagaaaag acatgaacga 3480actccaaaat atccatttaa tcaatcatgt ttttggcttt ggataaagaa ctttgaacca 3540gtttttttct caggagctgt caaatggaca cttaattatg acatgagaat gaagaaatta 3600ttttggaaaa aaaaaatgac ctaatttacc tatcagtgaa

agctttattt tctggtgcct 3660tttgaaagta tatggagtca tatcattctt ctgtttaaaa tgttagtttg gtttgacttt 3720ccactttgtc ctttctgctc ttgtgaagaa aaaaaaaagc attttcgagg aaagaattat 3780gcaatttctt ttgttttctg tgtcattatt tattgctttt tcaatgtgca gccagtggat 3840ggttttagtt ctttcagatg aactgccatt tgtgtttcag ctcacagttc tttgctgggt 3900aaaagaaata ctttctgaca gtcacctgag ccttaaatgt aagtattaca tgacatgcat 3960tctgtttctt ccagagttct gtctgccaca cgaaagagaa tatttgctta cttgatagaa 4020ctttggcatt ttcatcattc ttttacttaa ccaggcttat ggcatgatct ctggaacaaa 4080tttgtaggaa aaaattactc caattgaatg actgatgtat gtaatcaact tcattgggct 4140gcagtaaact agtggaaatt agagagttgt tttattggtg ttttctactg tgagttaatt 4200aaaaattgtt tttatttggg gtcattatgt cacagtcttg agttaacaag atcttacgtg 4260attggccttt tctttgtttt ctcttaggag ttgtgtctca tgaatgacag tactaaagct 4320attaacaact aagagtttga cagagaacta taagcctgtt gtatctccta aaagttgtca 4380actccccacc cttggacttt aaatgaaaat tttattcagt ccagctattc ttacagtccc 4440taaggatttt catatatcta tgtataggag ataaaatttg ctagtaagat ttttaaaaac 4500tggctagtga aaggaaagta cctctgaaag aaaccatttt agcaaattat ggttatatgt 4560tttaatttaa tctacagaat gttttatagt aaaattctag caccactaga ataatcacat 4620agcatgtaca atatatttat gctggctgaa aagacagaat ctgggaataa taaaattgca 4680accagtttgg taatgcaaac agcagaatag aatgaaatct cagtaatgaa ttaaagcaac 4740aaaaagatat tgattggcaa aaagcaagat ataagagatt catttgctta acatttctac 4800ataatattta tggtctggtc agtattggtc tggtcagtat tgcctggctg acgtgaaatg 4860taaactagta ggcgtgttat tgatctgcta aaactaaccc tctttttaag aggagattta 4920aggaagacgt caatcaaaat gtcaaatatg tgtgtcagaa tataaataat ttttcacatt 4980gtattgttgc tatataaaaa aaataataga attggttggg tttctgaggt gaaatccaga 5040gtaagagtac tagacagttc aacaagccac atctaatggc acagatagag gatgtagcta 5100ttttatacct ttcataacat ttgagagtaa gatatccttc aggatgtgaa gtgattatta 5160agtactcata cctgaaatct gttgtcaaga ttagaactgg ggttcatgtt aaaaaccttc 5220catattacct gagggtacct gtggggaaca gttccttccc ctgtgtggta gtattttgtt 5280ggaagagaat gtttatacaa aaaatgaaat tcttccaaca gcagagaaac tctaaaaagt 5340ttgatagtac ctatcaaagt gctgtacttc tgtgatagag aacatctgat gtaccaattt 5400agatctattt ctttatactt tttctaatca attgcttaat agtactttgg atgattatca 5460cctttgccac ttaaaatata taaatatcct ttttacttca tgaggaagga agaatttttt 5520gataattact gagttcagcc ttttgtgatg acttatattt tggacttaca ttttaacttt 5580aaagaatgtc agatcccttc tttgtcttac tagttaaatc ctcacctaat ctcttgggta 5640tgaatataaa tgtgtgtcat cgttatattg ttcagctaga tgagcaagta tcttagggta 5700gtaggtagcc tggtggtttt agaagtgttt ggtgattttt atggagagag ttttcctaag 5760tggtggttta taggtggtat cagatattat tagggcagct ttttggggag taatctcagg 5820tctcccagag cagcagcatt tttctcattg atataagtaa gattcttagg agcttttctt 5880atcacacaag atgcctgaat cgaatgtgag aattgaaggc atttcttctg cataaacaaa 5940gaattctacc tgctggacag aaacctggaa agttctttgg aattcgctga attacagttt 6000agtatgtcct gattacagag tgacaatatt tatcaagcct ttgttatatt ggattatctt 6060ctctcttaaa atacaactgt attataattg aaatgacagc ccaaaattgg atggtttacc 6120aaaaccaatg aaagggattt cacacatcaa tttttatttc tgttttgaag agcacatgct 6180atataataat tgctagtagc aactgcagta aaacaggtga taagttattt tctctgaaaa 6240gatccagtcc tagagcagga ttcttcgatc attcatggca gagtgaaaaa ggtttgtatg 6300gttcttgtcc aaataactca gttcttaaaa ttcttaaaat gatcgtaaac cattatcctt 6360taaaggttta tttgaagatg ctgttaaagt acagaatttt gtgtacaggt agatttttcc 6420gtccctcatt aatagtgcct tcttaattaa tacagactgg tgttagctat aacaaaactc 6480cagtaaggcc aaagaatccc aagttctttg tggaaaaaaa aaaaaaatct tttagggtca 6540gattttccct tctaatatca ttgaagatga tgttgcattg atttattcat aaagtatttt 6600aactatagga actctagaag ataatggtta ggcaagtgat ttttttttta aatatggttg 6660gcgtaagttg tattttgaaa ttcacttatt ttaaaatcga agaggattgt aatcatggaa 6720atagaatgtt tgtatctacc tgcccacatt ttcttaaaaa gatatttcat atacagataa 6780tgaagaccaa gctagtggct gcactgtagg tctgctgctt atttgtattt gttgtgcttc 6840tgtttatgtt gtagaagctg aaattctagc aacatgcttc aattctgtta ttttgatact 6900tatgaaaatg tattaggttt tactatattg tgcttttgaa agccataact cttaagaact 6960ttgtttttgc atattgtttg ctaattcttt actttaataa acctcaaaac ctgc 7014592886DNAHomo sapiens 59cgatcgaggg agctgagccg agagaaagag ccgccgggcg ctgcctcgcc agacctcgct 60gggaccccgg ggccaccggg aggcactttt gtggaggggg gagggggggc gacctcggca 120gcctcggcgc acgaagcgtc cgagggcagc gtggggcggg ctgcgacctc tgcatcggtg 180gactgcattt ttaattaagg attcccagca gctctttggg atttttacag cttccactca 240tgtgttgaca cccgcgtcca ggagaaactc gctccaagtg catctagcgc ctgggacctg 300agacggcgtt ggcctttcgt gcatgcaaat ccagggattt aggttttgtt tgggatttcc 360ttttctttct ttcctttttt ttttcttttt gcagggagta agaagggagc tgggggtatc 420aacaagcctg cctttcggat cctgcgggaa aagcccatgt agttaagcgc tttggtttaa 480aaaaaaggca aggtaaaggc agggctttcc agacacattt aggggttcgc gcgagcgctt 540tgtgctcatg gaccagccgc acaacttttg aaggctcgcc ggcccatgtg gggtctttct 600ggcggcgcgc cgcctgcagc ccccctaaag cgcgggggct ggagttgttg agcagccccg 660ccgctgtggt ccatgtagcc gctggccgcg cgcggactgc ggctcggcgt gcgcgtgttc 720ccggccgtcc cgcctcggcg agctccctca tgttgtcgcc ctgcggcgcc ccttcgacga 780caggctgtgc gcggtctgca cggcgctccg cggcggagct tcatgtgggg ctgcgacccg 840cgcagccggc gcctcgctga gggaacggac ccccggtaac cggagaccgc ctccccccca 900cccctggcgc caaaggatat cgtatgttca ggtccaaacg ctcggggctg gtgcggcgac 960tttggcgaag tcgtgtggtc cccgaccggg aggaaggcgg cagcggcggc ggcggtggcg 1020gcgacgagga tgggagcttg ggcagccgag ctgagccggc cccgcgggca agagagggcg 1080gaggctgcgg ccgctccgaa gtccgcccgg tagccccgcg gcggccccgg gacgcagtgg 1140gacagcgagg cgcccagggc gcggggaggc gccggcgcgc agggggcccc ccgaggccca 1200tgtcggagcc aggggccggc gctgggagct ccctgctgga cgtggcggag ccgggaggcc 1260cgggctggct gcccgagagt gactgcgaga cggtgacctg ctgtctcttt tcggagcggg 1320acgccgccgg cgcgccccgg gacgccagcg accccctggc cggggcggcc ctggagccgg 1380cgggcggcgg gcggagtcgc gaagcgcgct cgcggctgct gctgctggag caggaactca 1440aaaccgtcac gtactcgctg ctgaagcggc tcaaggagcg ctcgctggac acgctgctgg 1500aggcggtgga gtcccgcggc ggcgtgccgg gcggctgcgt gctggtgccg cgcgccgacc 1560tccgcctggg cggccagccc gcgccgccgc agctgctgct cggccgcctc tttcgctggc 1620ccgacctgca gcacgccgtg gagctgaagc ccctgtgcgg ctgccacagc ttcgccgccg 1680ccgccgacgg ccctaccgtg tgctgcaacc cctaccactt cagccggctc tgcgggcccg 1740aatctccgcc acctccctac tctcggctgt ctcctcgcga cgagtacaag ccactggatc 1800tgtccgattc cacattgtct tacactgaaa cggaggctac caactccctc atcactgctc 1860cgggtgaatt ctcagacgcc agcatgtctc cggacgccac caagccgagc cactggtgca 1920gcgtggcgta ctgggagcac cggacgcgcg tgggccgcct ctatgcggtg tacgaccagg 1980ccgtcagcat cttctacgac ctacctcagg gcagcggctt ctgcctgggc cagctcaacc 2040tggagcagcg cagcgagtcg gtgcggcgaa cgcgcagcaa gatcggcttc ggcatcctgc 2100tcagcaagga gcccgacggc gtgtgggcct acaaccgcgg cgagcacccc atcttcgtca 2160actccccgac gctggacgcg cccggcggcc gcgccctggt cgtgcgcaag gtgccccccg 2220gctactccat caaggtgttc gacttcgagc gctcgggcct gcagcacgcg cccgagcccg 2280acgccgccga cggcccctac gaccccaaca gcgtccgcat cagcttcgcc aagggctggg 2340ggccctgcta ctcccggcag ttcatcacct cctgcccctg ctggctggag atcctcctca 2400acaaccccag atagtggcgg ccccggcggg aggggcgggt gggaggccgc ggccaccgcc 2460acctgccggc ctcgagaggg gccgatgccc agagacacag cccccacgga caaaaccccc 2520cagatatcat ctacctagat ttaatataaa gttttatata ttatatggaa atatatatta 2580tacttgtaat tatggagtca tttttacaat gtaattattt atgtatggtg caatgtgtgt 2640atatggacaa aacaagaaag acgcactttg gcttataatt ctttcaatac agatatattt 2700tctttctctt cctccttcct cttccttact ttttatatat atatataaag aaaatgatac 2760agcagagcta ggtggaaaag cctgggtttg gtgtatggtt tttgagatat taatgcccag 2820acaaaaagct aataccagtc actcgataat aaagtattcg cattatagtt ttttttaaaa 2880aaaaaa 2886603088DNAHomo sapiens 60cggagagccg cgcagggcgc gggccgcgcg gggtggggca gccggagcgc aggcccccga 60tccccggcgg gcgcccccgg gcccccgcgc gcgccccggc ctccgggaga ctggcgcatg 120ccacggagcg cccctcgggc cgccgccgct cctgcccggg cccctgctgc tgctgctgtc 180gcctgcgcct gctgccccaa ctcggcgccc gacttcttca tggtgtgcgg aggtcatgtt 240cgctccttag caggcaaacg acttttctcc tcgcctcctc gccccgcatg ttcaggacca 300aacgatctgc gctcgtccgg cgtctctgga ggagccgtgc gcccggcggc gaggacgagg 360aggagggcgc agggggaggt ggaggaggag gcgagctgcg gggagaaggg gcgacggaca 420gccgagcgca tggggccggt ggcggcggcc cgggcagggc tggatgctgc ctgggcaagg 480cggtgcgagg tgccaaaggt caccaccatc cccacccgcc agccgcgggc gccggcgcgg 540ccgggggcgc cgaggcggat ctgaaggcgc tcacgcactc ggtgctcaag aaactgaagg 600agcggcagct ggagctgctg ctccaggccg tggagtcccg cggcgggacg cgcaccgcgt 660gcctcctgct gcccggccgc ctggactgca ggctgggccc gggggcgccc gccggcgcgc 720agcctgcgca gccgccctcg tcctactcgc tccccctcct gctgtgcaaa gtgttcaggt 780ggccggatct caggcattcc tcggaagtca agaggctgtg ttgctgtgaa tcttacggga 840agatcaaccc cgagctggtg tgctgcaacc cccatcacct tagccgactc tgcgaactag 900agtctccccc ccctccttac tccagatacc cgatggattt tctcaaacca actgcagact 960gtccagatgc tgtgccttcc tccgctgaaa cagggggaac gaattatctg gcccctgggg 1020ggctttcaga ttcccaactt cttctggagc ctggggatcg gtcacactgg tgcgtggtgg 1080catactggga ggagaagacg agagtgggga ggctctactg tgtccaggag ccctctctgg 1140atatcttcta tgatctacct caggggaatg gcttttgcct cggacagctc aattcggaca 1200acaagagtca gctggtgcag aaggtgcgga gcaaaatcgg ctgcggcatc cagctgacgc 1260gggaggtgga tggtgtgtgg gtgtacaacc gcagcagtta ccccatcttc atcaagtccg 1320ccacactgga caacccggac tccaggacgc tgttggtaca caaggtgttc cccggtttct 1380ccatcaaggc tttcgactac gagaaggcgt acagcctgca gcggcccaat gaccacgagt 1440ttatgcagca gccgtggacg ggctttaccg tgcagatcag ctttgtgaag ggctggggcc 1500agtgctacac ccgccagttc atcagcagct gcccgtgctg gctagaggtc atcttcaaca 1560gccggtagcc gcgtgcggag gggacagagc gtgagctgag caggccacac ttcaaactac 1620tttgctgcta atattttcct cctgagtgct tgcttttcat gcaaactctt tggtcgtttt 1680ttttttgttt gttggttggt tttcttcttc tcgtcctcgt ttgtgttctg ttttgtttcg 1740ctctttgaga aatagcttat gaaaagaatt gttgggggtt tttttggaag aaggggcagg 1800tatgatcggc aggacaccct gataggaaga ggggaagcag aaatccaagc accaccaaac 1860acagtgtatg aaggggggcg gtcatcattt cacttgtcag gagtgtgtgt gagtgtgagt 1920gtgcggctgt gtgtgcacgc gtgtgcagga gcggcagatg gggagacaac gtgctctttg 1980ttttgtgtct cttatggatg tccccagcag agaggtttgc agtcccaagc ggtgtctctc 2040ctgccccttg gacacgctca gtggggcaga ggcagtacct gggcaagctg gcggctgggg 2100tcccagcagc tgccaggagc acggctctgt ccccagcctg ggaaagcccc tgcccctcct 2160ctccctcatc aaggacacgg gcctgtccac aggcttctga gcagcgagcc tgctagtggc 2220cgaaccagaa ccaattattt tcatccttgt cttattccct tcctgccagc ccctgccatt 2280gtagcgtctt tcttttttgg ccatctgctc ctggatctcc ctgagatggg cttcccaagg 2340gctgccgggg cagccccctc acagtattgc tcacccagtg ccctctcccc tcagcctctc 2400ccctgcctgc cctggtgaca tcaggttttt cccggactta gaaaaccagc tcagcactgc 2460ctgctcccat cctgtgtgtt aagctctgct attaggccag caagcgggga tgtccctggg 2520agggacatgc ttagcagtcc ccttccctcc aagaaggatt tggtccgtca taacccaagg 2580taccatccta ggctgacacc taactcttct ttcatttctt ctacaactca tacactcgta 2640tgatacttcg acactgttct tagctcaatg agcatgttta gactttaaca taagctattt 2700ttctaactac aaaggtttaa atgaacaaga gaagcattct cattggaaat ttagcattgt 2760agtgctttga gagagaaagg actcctgaaa aaaaacctga gatttattaa agaaaaaaat 2820gtattttatg ttatatataa atatattatt acttgtaaat ataaagacgt tttataagca 2880tcattattta tgtattgtgc aatgtgtata aacaagaaaa ataaagaaaa gatgcacttt 2940gctttaatat aaatgcaaat aacaaatgcc aaattaaaaa agataaacac aagattggtg 3000tttttttcta tgggtgttat cacctagctg aatgtttttc taaaggagtt tatgttccat 3060taaacgattt ttaaaatgta cacttgaa 3088611722DNAHomo sapiens 61attcattgcg ccgcggcacg gcctagcgag tggttcttct gcgctactgc tgcgcgaatc 60ggcgacccca gtgcctcgac cactatgccg cgctctttcc tcgtcaggaa gccctccgac 120cccaatcgga agcctaacta cagcgagctg caggactcta atccagagtt taccttccag 180cagccctacg accaggccca cctgctggca gccatcccac ctccggagat cctcaacccc 240accgcctcgc tgccaatgct catctgggac tctgtcctgg cgccccaagc ccagccaatt 300gcctgggcct cccttcggct ccaggagagt cccagggtgg cagagctgac ctccctgtca 360gatgaggaca gtgggaaagg ctcccagccc cccagcccac cctcaccggc tccttcgtcc 420ttctcctcta cttcagtctc ttccttggag gccgaggcct atgctgcctt cccaggcttg 480ggccaagtgc ccaagcagct ggcccagctc tctgaggcca aggatctcca ggctcgaaag 540gccttcaact gcaaatactg caacaaggaa tacctcagcc tgggtgccct caagatgcac 600atccgaagcc acacgctgcc ctgcgtctgc ggaacctgcg ggaaggcctt ctctaggccc 660tggctgctac aaggccatgt ccggacccac actggcgaga agcccttctc ctgtccccac 720tgcagccgtg ccttcgctga ccgctccaac ctgcgggccc acctccagac ccactcagat 780gtcaagaagt accagtgcca ggcgtgtgct cggaccttct cccgaatgtc cctgctccac 840aagcaccaag agtccggctg ctcaggatgt ccccgctgac cctcgaggct ccctcttcct 900ctccatacct gcccctgcct gacagccttc cccagctcca gcaggaagga ccccacatcc 960ttctcactgc catggaattc cctcctgagt gccccacttc tggccacatc agccccacag 1020gactttgatg aagaccattt tctggttctg tgtcctctgc ctgggctctg gaagaggcct 1080tcccatggcc atttctgtgg agggagggca gctggccccc agccctgggg gattcctgag 1140ctggcctgtc tgcgtgggtt tttgtatcca gagctgtttg gatacagctg ctttgagcta 1200caggacaaag gctgacagac tcactgggaa gctcccaccc cactcagggg accccactcc 1260cctcacacac acccccccac aaggaaccct caggccaccc tccacgaggt gtgactaact 1320atgcaataat ccacccccag gtgcagcccc agggcctgcg gaggcggtgg cagactagag 1380tctgagatgc cccgagccca ggcagctatt tcagcctcct gtttggtggg gtggcacctg 1440tttcccgggc aatttaacaa tgtctgaaaa gggactgtga gtaatggctg tcacttgtcg 1500ggggcccaag tggggtgctc tggtctgacc gatgtgtctc ccagaactat tctgggggcc 1560cgacaggtgg gcctgggagg aagatgttta catttttaaa ggtacactgg tatttatatt 1620tcaaacattt tgtatcaagg aaacgttttg tatagttata tgtacagttt attgatattc 1680aataaagcag ttaatttata tattaaaaaa aaaaaaaaaa aa 1722622112DNAHomo sapiens 62aaaacgggct cagttcgtaa aggagccggg tgacttcaga ggcgccggcc cgtccgtctg 60ccgcacctga gcacggcccc tgcccgagcc tggcccgccg cgatgctgta gggaccgccg 120tgtcctcccg ccggaccgtt atccgcgccg ggcgcccgcc agacccgctg gcaagatgcc 180gcgctccttc ctggtcaaga agcatttcaa cgcctccaaa aagccaaact acagcgaact 240ggacacacat acagtgatta tttccccgta tctctatgag agttactcca tgcctgtcat 300accacaacca gagatcctca gctcaggagc atacagcccc atcactgtgt ggactaccgc 360tgctccattc cacgcccagc tacccaatgg cctctctcct ctttccggat actcctcatc 420tttggggcga gtgagtcccc ctcctccatc tgacacctcc tccaaggacc acagtggctc 480agaaagcccc attagtgatg aagaggaaag actacagtcc aagctttcag acccccatgc 540cattgaagct gaaaagtttc agtgcaattt atgcaataag acctattcaa ctttttctgg 600gctggccaaa cataagcagc tgcactgcga tgcccagtct agaaaatctt tcagctgtaa 660atactgtgac aaggaatatg tgagcctggg cgccctgaag atgcatattc ggacccacac 720attaccttgt gtttgcaaga tctgcggcaa ggcgttttcc agaccctggt tgcttcaagg 780acacattaga actcacacgg gggagaagcc tttttcttgc cctcactgca acagagcatt 840tgcagacagg tcaaatctga gggctcatct gcagacccat tctgatgtaa agaaatacca 900gtgcaaaaac tgctccaaaa ccttctccag aatgtctctc ctgcacaaac atgaggaatc 960tggctgctgt gtagcacact gagtgacgca atcaatgttt actcgaacag aatgcatttc 1020ttcactccga agccaaatga caaataaagt ccaaaggcat tttctcctgt gctgaccaac 1080caaataatat gtatagacac acacacatat gcacacacac acacacacac ccacagagag 1140agagctgcaa gagcatggaa ttcatgtgtt taaagataat cctttccatg tgaagtttaa 1200aattactata tatttgctga tggctagatt gagagaataa aagacagtaa cctttctctt 1260caaagataaa atgaaaagca cattgcatct tttcttccta aaaaaatgca aagatttaca 1320ttgctgccaa atcatttcaa ctgaaaagaa cagtattgct ttgtaataga gtctgtaata 1380ggatttccca taggaagaga tctgccagac gcgaactcag gtgccttaaa aagtattcca 1440agtttactcc attacatgtc ggttgtctgg ttgccattgt tgaactaaag cctttttttg 1500attacctgta gtgctttaaa gtatattttt aaaagggagg aaaaaaataa caagaacaaa 1560acacaggaga atgtattaaa agtatttttg ttttgttttg tttttgccaa ttaacagtat 1620gtgccttggg ggaggaggga aagattagct ttgaacattc ctggcgcatg ctccattgtc 1680ttactatttt aaaacatttt aataattttt gaaaattaat taaagatggg aataagtgca 1740aaagaggatt cttacaaatt cattaatgta cttaaactat ttcaaatgca taccacaaat 1800gcaataatac aatacccctt ccaagtgcct ttttaaattg tatagttgat gagtcaatgt 1860aaatttgtgt ttatttttat atgattgaat gagttctgta tgaaactgag atgttgtcta 1920tagctatgtc tataaacaac ctgaagactt gtgaaatcaa tgtttctttt ttaaaaaaca 1980attttcaagt tttttttaca ataaacagtt ttgatttaaa atctcgtttg tatactattt 2040tcagagactt tacttgcttc atgattagta ccaaaccact gtacaaagaa ttgtttgtta 2100acaagaaaaa aa 2112633173DNAHomo sapiens 63cggcgggcgg cagcagccta ggcagcagca gtagcagaag cagcagccgc cgagcagcag 60caaggactct ggagtcagag taggactgta ggaccggagc ctgagtggaa caggagtgga 120gctggcctgg gagagagcgg atccctccca gcaccctcag gccacccgtt gcctgcactc 180tccctgccag acctccagag aggagagact cgggacagcc agccccaggt tcccccagct 240ctctccatct gcctggctcc ttgggacccg ttccccagcc tcaggatggc gtcctccctg 300cttgaggagg aagttcacta tggctccagt cccctggcca tgctgacggc agcgtgcagc 360aaatttggtg gctctagccc tctgcgggac tcaacaactc tgggcaaagc aggcacaaag 420aagccgtact ctgtgggcag tgacctttca gcctccaaaa ccatggggga tgcttatcca 480gcccccttta caagcactaa tgggctcctt tcacctgcag gcagtcctcc agcacccacc 540tcaggctatg ctaatgatta ccctcccttt tcccactcat tccctgggcc cacaggcacc 600caggaccctg ggctactagt gcccaagggg cacagctctt ctgactgtct gcccagtgtc 660tacacctctc tggacatgac acacccctat ggctcctggt acaaggcagg catccatgca 720ggcatttcac caggcccagg caacactcct actccatggt gggatatgca ccctggaggc 780aactggctag gtggtgggca gggccagggt gatgggctgc aagggacact gcccacaggt 840ccagctcagc ctccactgaa cccccagctg cccacctacc catctgactt tgctcccctt 900aatccagccc cctacccagc tccccacctc ttgcaaccag ggccccagca tgtcttgccc 960caagatgtct ataaacccaa ggcagtggga aatagtgggc agctagaagg gagtggtgga 1020gccaaacccc cacggggtgc aagcactggg ggtagtggtg gatatggggg cagtggggca 1080gggcgctcct cctgcgactg ccctaattgc caggagctag agcggctggg agcagcagcg 1140gctgggctgc ggaagaagcc catccacagc tgccacatcc ctggctgcgg caaggtgtat 1200ggcaaggctt cgcacctgaa ggcccacttg cgctggcaca caggcgagag gcccttcgtc 1260tgcaactggc tcttctgcgg caagaggttc actcgttcgg atgagctgga gcgtcatgtg 1320cgcactcaca cccgggagaa gaagttcacc tgcctgctct gctccaagcg ctttacccga 1380agcgaccacc tgagcaaaca ccagcgcacc catggagaac caggcccggg tccccctccc 1440agtggcccca aggagctggg ggagggccgc agcacggggg aagaggaggc cagtcagacg 1500ccccgacctt ctgcctcgcc agcaacccca gagaaagccc ctggaggcag ccctgagcag 1560agcaacttgc tggagatctg agccgggtgg aaggtctccc accccagggc tgccctgaca

1620gtctctcttg gctctctaga ccactgcttg ccaatcactc tctttacccc atgcatgcca 1680tccttcgggg ctctctccct ctgtctccct cctggccatt ctgggcttgg gtatctcctt 1740gcatgcctcc tcagctcacc ttctctcttc accatgagac tggctttcca caaactctca 1800tctcaggccc tccccttgtg cctgatacct gcactccggc ttcctagact ctggccctgc 1860cacaccaaca cactttctat ttgggctccc aacactattt ctccatctca ctccttgaca 1920tgtacccctt tctgcttctc aagcttattt cctgctgtcc ctcagcctcc aggcttcagt 1980cttcccaact tcttacacca ttgctttcca ttctccagaa ctcttttttc ctttttacaa 2040acacaatgat aatgataatt tattgccccc tggtggcctc ttcatcaggg gtattggggt 2100tagtgacctg gccagagggt gccaagaggg gggcagacca gtggggatct gatcccaaag 2160atggggtgac cccagggtca gggaggctgc ccccaggcct gtatatttaa cccctatgta 2220ccaggagtaa tgaatagtaa taattctatt tatgtaagtt atgatgacgg gtcaggtaga 2280gtgagctggg gagggaagtg gatccatttc tgctaaggaa attctagtca aatgcatctc 2340tgtatagaca aaatgttagt ggagaagatc ttgttaatag aatgtctatc atcagaatct 2400cagttgatag ggtttctctt gtaatgaagt ctctacaaat tgggttagct acatctctgc 2460taaacagttg atggggtatc tcttgattag ggggatccct aatatcccca gccccagcca 2520gaagctgtga aacctcaagt cctatggagg ggagaaggac tggaatgtac cccatctccc 2580ttgactgcag agcaggttcc tccactgccc caccccttag acaccatgac cccatcaggt 2640taatcccctg ttgccatggt tatggagagc ttgcagctgc catcttagat gtgctctttg 2700gggaagccca tctaacagga ggacattggt ttgggggtgc acctcctgaa gaatgggtgg 2760ggaaggcttt ctctaggatc agattcaaat aagtatgtat tgagtgccta ctctgtgcaa 2820ggcactatgc tagatctggt gcctagaagc cctgagaaag aacttaaaga gctaggagga 2880cagaggcccc caagctgatc tggtggtgca tccacgcacc cccaccctgg gactttggat 2940gctcccatct ccacctccag tgacttttaa agccgcttcg tgcctttcct gtaacgttgg 3000atcctccttt tctgtcccct gctgtctcaa ggccccaagt taaagggtta aagccgctgg 3060agcttgggga gagaacattg tggaatggaa gggatcatgc cctttgtgga gtcttttttt 3120tttaatttaa taaataaaag ttggatttga aaaaaaaaaa aaaaaaaaaa aaa 3173641616DNAHomo sapiens 64ctccctgtgt tggtggagga tgtctgcagc agcatttaaa ttctgggagg gcttggttgt 60cagcagcagc aggaggaggc agagcacagc atcgtcggga ccagactcgt ctcaggccag 120ttgcagcctt ctcagccaaa cgccgaccaa ggaaaactca ctaccatgag aattgcagtg 180atttgctttt gcctcctagg catcacctgt gccataccag ttaaacaggc tgattctgga 240agttctgagg aaaagcagct ttacaacaaa tacccagatg ctgtggccac atggctaaac 300cctgacccat ctcagaagca gaatctccta gccccacaga cccttccaag taagtccaac 360gaaagccatg accacatgga tgatatggat gatgaagatg atgatgacca tgtggacagc 420caggactcca ttgactcgaa cgactctgat gatgtagatg acactgatga ttctcaccag 480tctgatgagt ctcaccattc tgatgaatct gatgaactgg tcactgattt tcccacggac 540ctgccagcaa ccgaagtttt cactccagtt gtccccacag tagacacata tgatggccga 600ggtgatagtg tggtttatgg actgaggtca aaatctaaga agtttcgcag acctgacatc 660cagtaccctg atgctacaga cgaggacatc acctcacaca tggaaagcga ggagttgaat 720ggtgcataca aggccatccc cgttgcccag gacctgaacg cgccttctga ttgggacagc 780cgtgggaagg acagttatga aacgagtcag ctggatgacc agagtgctga aacccacagc 840cacaagcagt ccagattata taagcggaaa gccaatgatg agagcaatga gcattccgat 900gtgattgata gtcaggaact ttccaaagtc agccgtgaat tccacagcca tgaatttcac 960agccatgaag atatgctggt tgtagacccc aaaagtaagg aagaagataa acacctgaaa 1020tttcgtattt ctcatgaatt agatagtgca tcttctgagg tcaattaaaa ggagaaaaaa 1080tacaatttct cactttgcat ttagtcaaaa gaaaaaatgc tttatagcaa aatgaaagag 1140aacatgaaat gcttctttct cagtttattg gttgaatgtg tatctatttg agtctggaaa 1200taactaatgt gtttgataat tagtttagtt tgtggcttca tggaaactcc ctgtaaacta 1260aaagcttcag ggttatgtct atgttcattc tatagaagaa atgcaaacta tcactgtatt 1320ttaatatttg ttattctctc atgaatagaa atttatgtag aagcaaacaa aatactttta 1380cccacttaaa aagagaatat aacattttat gtcactataa tcttttgttt tttaagttag 1440tgtatatttt gttgtgatta tctttttgtg gtgtgaataa atcttttatc ttgaatgtaa 1500taagaatttg gtggtgtcaa ttgcttattt gttttcccac ggttgtccag caattaataa 1560aacataacct tttttactgc ctaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaa 1616651574DNAHomo sapiens 65tcaccacggc ggcagccctt taaacccctc acccagccag cgccccatcc tgtctgtccg 60aacccagaca caagtcttca ctccttcctg cgagccctga ggaagccttg tgagtgcatt 120ggctggggct tggagggaag ttgggctgga gctggacagg agcagtgggt gcatttcagg 180caggctctcc tgaggtccca ggcgccagct ccagctccct ggctagggaa acccaccctc 240tcagtcagca tgggggccca agctccaggc agggtgggct ggatcactag cgtcctggat 300ctctctcaga ctgggcagcc ccgggctcat tgaaatgccc cggatgactt ggctagtgca 360gaggaattga tggaaaccac cggggtgaga gggaggctcc ccatctcagc cagccacatc 420cacaaggtgt gtgtaagggt gcaggcgccg gccggttagg ccaaggctct actgtctgtt 480gcccctccag gagaacttcc aaggagcttt ccccagacat ggccaacaag ggtccttcct 540atggcatgag ccgcgaagtg cagtccaaaa tcgagaagaa gtatgacgag gagctggagg 600agcggctggt ggagtggatc atagtgcagt gtggccctga tgtgggccgc ccagaccgtg 660ggcgcttggg cttccaggtc tggctgaaga atggcgtgat tctgagcaag ctggtgaaca 720gcctgtaccc tgatggctcc aagccggtga aggtgcccga gaacccaccc tccatggtct 780tcaagcagat ggagcaggtg gctcagttcc tgaaggcggc tgaggactat ggggtcatca 840agactgacat gttccagact gttgacctct ttgaaggcaa agacatggca gcagtgcaga 900ggaccctgat ggctttgggc agcttggcag tgaccaagaa tgatgggcac taccgtggag 960atcccaactg gtttatgaag aaagcgcagg agcataagag ggaattcaca gagagccagc 1020tgcaggaggg aaagcatgtc attggccttc agatgggcag caacagaggg gcctcccagg 1080ccggcatgac aggctacgga cgacctcggc agatcatcag ttagagcgga gagggctagc 1140cctgagcccg gccctccccc agctccttgg ctgcagccat cccgcttagc ctgcctcacc 1200cacacccgtg tggtaccttc agccctggcc aagctttgag gctctgtcac tgagcaatgg 1260taactgcacc tgggcagctc ctccctgtgc ccccagcctc agcccaactt cttacccgaa 1320agcatcactg ccttggcccc tccctcccgg ctgcccccat cacctctact gtctcctccc 1380tgggctaagc aggggagaag cgggctgggg gtagcctgga tgtgggccaa gtccactgtc 1440ctccttggcg gcaaaagccc attgaagaag aaccagccca gcctgccccc tatcttgtcc 1500tggaatattt ttggggttgg aactcaaaaa aaaaaaaaaa aaatcaatct tttctcaaaa 1560aaaaaaaaaa aaaa 1574663829DNAHomo sapiens 66caggcagcgc tgcgtcctgc tgcgcacgtg ggaagccctg gccccggcca cccccgcgat 60gccgcgcgct ccccgctgcc gagccgtgcg ctccctgctg cgcagccact accgcgaggt 120gctgccgctg gccacgttcg tgcggcgcct ggggccccag ggctggcggc tggtgcagcg 180cggggacccg gcggctttcc gcgcgctggt ggcccagtgc ctggtgtgcg tgccctggga 240cgcacggccg ccccccgccg ccccctcctt ccgccaggtg tcctgcctga aggagctggt 300ggcccgagtg ctgcagaggc tgtgcgagcg cggcgcgaag aacgtgctgg ccttcggctt 360cgcgctgctg gacggggccc gcgggggccc ccccgaggcc ttcaccacca gcgtgcgcag 420ctacctgccc aacacggtga ccgacgcact gcgggggagc ggggcgtggg ggctgctgct 480gcgccgcgtg ggcgacgacg tgctggttca cctgctggca cgctgcgcgc tctttgtgct 540ggtggctccc agctgcgcct accaggtgtg cgggccgccg ctgtaccagc tcggcgctgc 600cactcaggcc cggcccccgc cacacgctag tggaccccga aggcgtctgg gatgcgaacg 660ggcctggaac catagcgtca gggaggccgg ggtccccctg ggcctgccag ccccgggtgc 720gaggaggcgc gggggcagtg ccagccgaag tctgccgttg cccaagaggc ccaggcgtgg 780cgctgcccct gagccggagc ggacgcccgt tgggcagggg tcctgggccc acccgggcag 840gacgcgtgga ccgagtgacc gtggtttctg tgtggtgtca cctgccagac ccgccgaaga 900agccacctct ttggagggtg cgctctctgg cacgcgccac tcccacccat ccgtgggccg 960ccagcaccac gcgggccccc catccacatc gcggccacca cgtccctggg acacgccttg 1020tcccccggtg tacgccgaga ccaagcactt cctctactcc tcaggcgaca aggagcagct 1080gcggccctcc ttcctactca gctctctgag gcccagcctg actggcgctc ggaggctcgt 1140ggagaccatc tttctgggtt ccaggccctg gatgccaggg actccccgca ggttgccccg 1200cctgccccag cgctactggc aaatgcggcc cctgtttctg gagctgcttg ggaaccacgc 1260gcagtgcccc tacggggtgc tcctcaagac gcactgcccg ctgcgagctg cggtcacccc 1320agcagccggt gtctgtgccc gggagaagcc ccagggctct gtggcggccc ccgaggagga 1380ggacacagac ccccgtcgcc tggtgcagct gctccgccag cacagcagcc cctggcaggt 1440gtacggcttc gtgcgggcct gcctgcgccg gctggtgccc ccaggcctct ggggctccag 1500gcacaacgaa cgccgcttcc tcaggaacac caagaagttc atctccctgg ggaagcatgc 1560caagctctcg ctgcaggagc tgacgtggaa gatgagcgtg cgggactgcg cttggctgcg 1620caggagccca ggggttggct gtgttccggc cgcagagcac cgtctgcgtg aggagatcct 1680ggccaagttc ctgcactggc tgatgagtgt gtacgtcgtc gagctgctca ggtctttctt 1740ttatgtcacg gagaccacgt ttcaaaagaa caggctcttt ttctaccgga agagtgtctg 1800gagcaagttg caaagcattg gaatcagaca gcacttgaag agggtgcagc tgcgggagct 1860gtcggaagca gaggtcaggc agcatcggga agccaggccc gccctgctga cgtccagact 1920ccgcttcatc cccaagcctg acgggctgcg gccgattgtg aacatggact acgtcgtggg 1980agccagaacg ttccgcagag aaaagagggc cgagcgtctc acctcgaggg tgaaggcact 2040gttcagcgtg ctcaactacg agcgggcgcg gcgccccggc ctcctgggcg cctctgtgct 2100gggcctggac gatatccaca gggcctggcg caccttcgtg ctgcgtgtgc gggcccagga 2160cccgccgcct gagctgtact ttgtcaaggt ggatgtgacg ggcgcgtacg acaccatccc 2220ccaggacagg ctcacggagg tcatcgccag catcatcaaa ccccagaaca cgtactgcgt 2280gcgtcggtat gccgtggtcc agaaggccgc ccatgggcac gtccgcaagg ccttcaagag 2340ccacgtctct accttgacag acctccagcc gtacatgcga cagttcgtgg ctcacctgca 2400ggagaccagc ccgctgaggg atgccgtcgt catcgagcag agctcctccc tgaatgaggc 2460cagcagtggc ctcttcgacg tcttcctacg cttcatgtgc caccacgccg tgcgcatcag 2520gggcaagtcc tacgtccagt gccaggggat cccgcagggc tccatcctct ccacgctgct 2580ctgcagcctg tgctacggcg acatggagaa caagctgttt gcggggattc ggcgggacgg 2640gctgctcctg cgtttggtgg atgatttctt gttggtgaca cctcacctca cccacgcgaa 2700aaccttcctc agctatgccc ggacctccat cagagccagt ctcaccttca accgcggctt 2760caaggctggg aggaacatgc gtcgcaaact ctttggggtc ttgcggctga agtgtcacag 2820cctgtttctg gatttgcagg tgaacagcct ccagacggtg tgcaccaaca tctacaagat 2880cctcctgctg caggcgtaca ggtttcacgc atgtgtgctg cagctcccat ttcatcagca 2940agtttggaag aaccccacat ttttcctgcg cgtcatctct gacacggcct ccctctgcta 3000ctccatcctg aaagccaaga acgcagggat gtcgctgggg gccaagggcg ccgccggccc 3060tctgccctcc gaggccgtgc agtggctgtg ccaccaagca ttcctgctca agctgactcg 3120acaccgtgtc acctacgtgc cactcctggg gtcactcagg acagcccaga cgcagctgag 3180tcggaagctc ccggggacga cgctgactgc cctggaggcc gcagccaacc cggcactgcc 3240ctcagacttc aagaccatcc tggactgatg gccacccgcc cacagccagg ccgagagcag 3300acaccagcag ccctgtcacg ccgggctcta cgtcccaggg agggaggggc ggcccacacc 3360caggcccgca ccgctgggag tctgaggcct gagtgagtgt ttggccgagg cctgcatgtc 3420cggctgaagg ctgagtgtcc ggctgaggcc tgagcgagtg tccagccaag ggctgagtgt 3480ccagcacacc tgccgtcttc acttccccac aggctggcgc tcggctccac cccagggcca 3540gcttttcctc accaggagcc cggcttccac tccccacata ggaatagtcc atccccagat 3600tcgccattgt tcacccctcg ccctgccctc ctttgccttc cacccccacc atccaggtgg 3660agaccctgag aaggaccctg ggagctctgg gaatttggag tgaccaaagg tgtgccctgt 3720acacaggcga ggaccctgca cctggatggg ggtccctgtg ggtcaaattg gggggaggtg 3780ctgtgggagt aaaatactga atatatgagt ttttcagttt tgaaaaaaa 3829676244DNAHomo sapiens 67ggcgaggcga ggtttgctgg ggtgaggcag cggcgcggcc gggccgggcc gggccacagg 60cggtggcggc gggaccatgg aggcggcggt cgctgctccg cgtccccggc tgctcctcct 120cgtgctggcg gcggcggcgg cggcggcggc ggcgctgctc ccgggggcga cggcgttaca 180gtgtttctgc cacctctgta caaaagacaa ttttacttgt gtgacagatg ggctctgctt 240tgtctctgtc acagagacca cagacaaagt tatacacaac agcatgtgta tagctgaaat 300tgacttaatt cctcgagata ggccgtttgt atgtgcaccc tcttcaaaaa ctgggtctgt 360gactacaaca tattgctgca atcaggacca ttgcaataaa atagaacttc caactactgg 420tttaccattg cttgttcaga gaacaattgc gagaactatt gtgttacaag aaagcattgg 480caaaggtcga tttggagaag tttggagagg aaagtggcgg ggagaagaag ttgctgttaa 540gatattctcc tctagagaag aacgttcgtg gttccgtgag gcagagattt atcaaactgt 600aatgttacgt catgaaaaca tcctgggatt tatagcagca gacaataaag acaatggtac 660ttggactcag ctctggttgg tgtcagatta tcatgagcat ggatcccttt ttgattactt 720aaacagatac acagttactg tggaaggaat gataaaactt gctctgtcca cggcgagcgg 780tcttgcccat cttcacatgg agattgttgg tacccaagga aagccagcca ttgctcatag 840agatttgaaa tcaaagaata tcttggtaaa gaagaatgga acttgctgta ttgcagactt 900aggactggca gtaagacatg attcagccac agataccatt gatattgctc caaaccacag 960agtgggaaca aaaaggtaca tggcccctga agttctcgat gattccataa atatgaaaca 1020ttttgaatcc ttcaaacgtg ctgacatcta tgcaatgggc ttagtattct gggaaattgc 1080tcgacgatgt tccattggtg gaattcatga agattaccaa ctgccttatt atgatcttgt 1140accttctgac ccatcagttg aagaaatgag aaaagttgtt tgtgaacaga agttaaggcc 1200aaatatccca aacagatggc agagctgtga agccttgaga gtaatggcta aaattatgag 1260agaatgttgg tatgccaatg gagcagctag gcttacagca ttgcggatta agaaaacatt 1320atcgcaactc agtcaacagg aaggcatcaa aatgtaattc tacagctttg cctgaactct 1380ccttttttct tcagatctgc tcctgggttt taatttggga ggtcaattgt tctacctcac 1440tgagagggaa cagaaggata ttgcttcctt ttgcagcagt gtaataaagt caattaaaaa 1500cttcccagga tttctttgga cccaggaaac agccatgtgg gtcctttctg tgcactatga 1560acgcttcttt cccaggacag aaaatgtgta gtctaccttt attttttatt aacaaaactt 1620gttttttaaa aagatgattg ctggtcttaa ctttaggtaa ctctgctgtg ctggagatca 1680tctttaaggg caaaggagtt ggattgctga attacaatga aacatgtctt attactaaag 1740aaagtgattt actcctggtt agtacattct cagaggattc tgaaccacta gagtttcctt 1800gattcagact ttgaatgtac tgttctatag tttttcagga tcttaaaact aacacttata 1860aaactcttat cttgagtcta aaaatgacct catatagtag tgaggaacat aattcatgca 1920attgtatttt gtatactatt attgttcttt cacttattca gaacattaca tgccttcaaa 1980atgggattgt actataccag taagtgccac ttctgtgtct ttctaatgga aatgagtaga 2040attgctgaaa gtctctatgt taaaacctat agtgtttgaa ttcaaaaagc ttatttatct 2100gggtaaccca aactttttct gttttgtttt tggaagggtt tttgtggtat gtcatttggt 2160attctattct gaaaatgcct ttctcctacc aaaatgtgct taagccacta aagaaatgaa 2220gtggcattaa ttagtaaatt attagcatgg tcatgtttga atattctcac atcaagcttt 2280tgcattttaa ttgtgttgtc taagtatact tttaaaaaat caagtggcac tctagatgct 2340tatagtactt taatatttgt agcatacaga ctaatttttc taaaagggaa agtctgtcta 2400gctgcttgtg aaaagttatg tggtattctg taagccattt ttttctttat ctgttcaaag 2460acttattttt taagacatga attacattta aaattagaat atggttaata ttaaataata 2520ggcctttttc taggaaggcg aaggtagtta ataatttgaa tagataacag atgtgcaaga 2580aagtcacatt tgttatgtat gtaggagtaa acgttcggtg gatcctctgt ctttgtaact 2640gaggttagag ctagtgtggt tttgaggtct cactacactt tgaggaaggc agcttttaat 2700tcagtgtttc cttatgtgtg cgtacattgc aactgcttac atgtaattta tgtaatgcat 2760tcagtgcacc cttgttactt gggagaggtg gtagctaaag aacattctga gtataggttt 2820ttctccattt acagatgtct ttggtcaaat attgaaagca aacttgtcat ggtcttctta 2880cattaagttg aaactagctt ataataactg gtttttactt ccaatgctat gaagtctctg 2940cagggctttt acagttttcg aagtcctttt atcactgtga tcttattctg aggggagaaa 3000aaactatcat agctctgagg caagacttcg actttatagt gctatcagtt ccccgataca 3060gggtcagagt aacccataca gtattttggt caggaagaga aagtggccat ttacactgaa 3120tgagttgcat tctgataatg tcttatctct tatacgtaga ataaatttga aagactattt 3180gatcttaaaa ccaaagtaat tttagaatga gtgacatatt acataggaat ttagtgtcaa 3240tttcatgtgt ttaaaaacat catgggaaaa atgcttagag gttactattt tgactacaaa 3300gttgagtttt tttctgtagt taccataatt tcattgaagc aaatgaatga gtttgagagg 3360tttgttttta tagttgtgtt gtattacttg tttaataata atctctaatt ctgtgatcag 3420gtactttttt tgtgggggtt ttttttttgt tttttttttt ttgttgttgt ttttgggcca 3480tttctaagcc taccagatct gctttatgaa atccagggga ccaatgcatt ttatcactaa 3540aactattttt atataatttt aagaatatac caaaagttgt ctgatttaaa gttgtaatac 3600atgatttctc actttcatgt aaggttatcc acttttgctg aagatatttt ttattgaatc 3660aaagattgag ttacaattat acttttctta cctaagtgga taaaatgtac ttttgatgaa 3720tcagggaatt tttttaaagt tggagtttag ttctaaattg actttacgta ttactgcagt 3780taattccttt tttggctagg gatggtttga taaaccacaa ttggctgata ttgaaaatga 3840aagaaactta aaaggtggga tggatcatga ttactgtcga taactgcaga taaatttgat 3900tagagtaata attttgtcat ttaaaaacac agttgtttat actgcccatc ctaggatgct 3960caccttccaa gattcaacgt ggctaaaaca tcttctggta aattgtgcgt ccatattcat 4020tttgtcagta gccaggagaa atggggatgg gggaaatacg acttagtgag gcatagacat 4080ccctggtcca tcctttctgt ctccagctgt ttcttggaac ctgctctcct gcttgctggt 4140ccctgacgca gagaccgttg cctcccccac agccgtttga ctgaaggctg ctctggagac 4200ctagagtaaa acggctgatg gaagttgtgg gacccacttc catttccttc agtcattaga 4260ggtggaaggg aggggtctcc aagtttggag attgagcaga tgaggcttgg gatgcccctg 4320ctttgacttc agccatggat gaggagtggg atggcagcaa ggtggctcct gtggcagtgg 4380agttgtgcca gaaacagtgg ccagttgtat cgcctataag acagggtaag gtctgaagag 4440ctgagcctgt aattctgctg taataatgat agtgctcaag aagtgccttg agttggtgta 4500cagtgccatg gccatcaaga atcccagatt tcaggtttta ttacaaaatg taagtggtca 4560cttggcgatt ttgtagtaca tgcatgagtt accttttttc tctatgtctg agaactgtca 4620gattaaaaca agatggcaaa gagatcgtta gagtgcacaa caaaatcact atcccattag 4680acacatcatc aaaagcttat ttttattctt gcactggaag aatcgtaagt caactgtttc 4740ttgaccatgg cagtgttctg gctccaaatg gtagtgattc caaataatgg ttctgttaac 4800actttggcag aaaatgccag ctcagatatt ttgagatact aaggattatc tttggacatg 4860tactgcagct tcttgtctct gttttggatt actggaatac ccatgggccc tctcaagagt 4920gctggacttc taggacatta agatgattgt cagtacatta aacttttcaa tcccattatg 4980caatcttgtt tgtaaatgta aacttctaaa aatatggtta ataacattca acctgtttat 5040tacaacttaa aaggaacttc agtgaatttg tttttatttt ttaacaagat ttgtgaactg 5100aatatcatga accatgtttt gatacccctt tttcacgttg tgccaacgga atagggtgtt 5160tgatatttct tcatatgtta aggagatgct tcaaaatgtc aattgcttta aacttaaatt 5220acctctcaag agaccaaggt acatttacct cattgtgtat ataatgttta atatttgtca 5280gagcattctc caggtttgca gttttatttc tataaagtat gggtattatg ttgctcagtt 5340actcaaatgg tactgtattg tttatatttg taccccaaat aacatcgtct gtactttctg 5400ttttctgtat tgtatttgtg caggattctt taggctttat cagtgtaatc tctgcctttt 5460aagatatgta cagaaaatgt ccatataaat ttccattgaa gtcgaatgat actgagaagc 5520ctgtaaagag gagaaaaaaa cataagctgt gtttccccat aagttttttt aaattgtata 5580ttgtatttgt agtaatattc caaaagaatg taaataggaa atagaagagt gatgcttatg 5640ttaagtccta acactacagt agaagaatgg aagcagtgca aataaattac atttttccca 5700agtgccagtg gcatatttta aaataaagtg tatacgttgg aatgagtcat gccatatgta 5760gttgctgtag atggcaacta gaacctttga gttacaagag tctttagaag ttttctaacc 5820ctgcctagtg caagttacaa tattatagcg tgttcgggga gtgccctcct gtctgcaggt 5880gtgtctctgt gcctgggggc ttttctccac atgcttaggg gtgtgggtct tccattgggg 5940catgatggac ctgtctacag gtgatctctg ttgcctttgg gtcagcacat ttgttagtct 6000cctgggggtg aaaacttggc ttacaagaga actggaaaaa tgatgagatg tggtccccaa 6060acccttgatt gactctgggg aggggctttg tgaataggat tgctctcaca ttaaagatag 6120ttacttcaat ttgaaggctg gatttaggga tttttttttt tccttataac aaagacatca 6180ccaggatatg aagcttttgt tgaaagttgg aaaaaaagtg aaattaaaga cattcccaga 6240caaa 624468931DNAHomo sapiens 68tttcgtcggc ccgccccttg

gcttctgcac tgatggtggg tggatgagta atgcatccag 60gaagcctgga ggcctgtggt ttccgcaccc gctgccaccc ccgcccctag cgtggacatt 120tatcctctag cgctcaggcc ctgccgccat cgccgcagat ccagcgccca gagagacacc 180agagaaccca ccatggcccc ctttgagccc ctggcttctg gcatcctgtt gttgctgtgg 240ctgatagccc ccagcagggc ctgcacctgt gtcccacccc acccacagac ggccttctgc 300aattccgacc tcgtcatcag ggccaagttc gtggggacac cagaagtcaa ccagaccacc 360ttataccagc gttatgagat caagatgacc aagatgtata aagggttcca agccttaggg 420gatgccgctg acatccggtt cgtctacacc cccgccatgg agagtgtctg cggatacttc 480cacaggtccc acaaccgcag cgaggagttt ctcattgctg gaaaactgca ggatggactc 540ttgcacatca ctacctgcag ttttgtggct ccctggaaca gcctgagctt agctcagcgc 600cggggcttca ccaagaccta cactgttggc tgtgaggaat gcacagtgtt tccctgttta 660tccatcccct gcaaactgca gagtggcact cattgcttgt ggacggacca gctcctccaa 720ggctctgaaa agggcttcca gtcccgtcac cttgcctgcc tgcctcggga gccagggctg 780tgcacctggc agtccctgcg gtcccagata gcctgaatcc tgcccggagt ggaagctgaa 840gcctgcacag tgtccaccct gttcccactc ccatctttct tccggacaat gaaataaaga 900gttaccaccc agcagaaaaa aaaaaaaaaa a 931693677DNAHomo sapiens 69tcgcggaggc ttggggcagc cgggtagctc ggaggtcgtg gcgctggggg ctagcaccag 60cgctctgtcg ggaggcgcag cggttaggtg gaccggtcag cggactcacc ggccagggcg 120ctcggtgctg gaatttgata ttcattgatc cgggttttat ccctcttctt ttttcttaaa 180catttttttt taaaactgta ttgtttctcg ttttaattta tttttgcttg ccattcccca 240cttgaatcgg gccgacggct tggggagatt gctctacttc cccaaatcac tgtggatttt 300ggaaaccagc agaaagagga aagaggtagc aagagctcca gagagaagtc gaggaagaga 360gagacggggt cagagagagc gcgcgggcgt gcgagcagcg aaagcgacag gggcaaagtg 420agtgacctgc ttttgggggt gaccgccgga gcgcggcgtg agccctcccc cttgggatcc 480cgcagctgac cagtcgcgct gacggacaga cagacagaca ccgcccccag ccccagctac 540cacctcctcc ccggccggcg gcggacagtg gacgcggcgg cgagccgcgg gcaggggccg 600gagcccgcgc ccggaggcgg ggtggagggg gtcggggctc gcggcgtcgc actgaaactt 660ttcgtccaac ttctgggctg ttctcgcttc ggaggagccg tggtccgcgc gggggaagcc 720gagccgagcg gagccgcgag aagtgctagc tcgggccggg aggagccgca gccggaggag 780ggggaggagg aagaagagaa ggaagaggag agggggccgc agtggcgact cggcgctcgg 840aagccgggct catggacggg tgaggcggcg gtgtgcgcag acagtgctcc agccgcgcgc 900gctccccagg ccctggcccg ggcctcgggc cggggaggaa gagtagctcg ccgaggcgcc 960gaggagagcg ggccgcccca cagcccgagc cggagaggga gcgcgagccg cgccggcccc 1020ggtcgggcct ccgaaaccat gaactttctg ctgtcttggg tgcattggag ccttgccttg 1080ctgctctacc tccaccatgc caagtggtcc caggctgcac ccatggcaga aggaggaggg 1140cagaatcatc acgaagtggt gaagttcatg gatgtctatc agcgcagcta ctgccatcca 1200atcgagaccc tggtggacat cttccaggag taccctgatg agatcgagta catcttcaag 1260ccatcctgtg tgcccctgat gcgatgcggg ggctgctgca atgacgaggg cctggagtgt 1320gtgcccactg aggagtccaa catcaccatg cagattatgc ggatcaaacc tcaccaaggc 1380cagcacatag gagagatgag cttcctacag cacaacaaat gtgaatgcag accaaagaaa 1440gatagagcaa gacaagaaaa aaaatcagtt cgaggaaagg gaaaggggca aaaacgaaag 1500cgcaagaaat cccggtataa gtcctggagc gtgtacgttg gtgcccgctg ctgtctaatg 1560ccctggagcc tccctggccc ccatccctgt gggccttgct cagagcggag aaagcatttg 1620tttgtacaag atccgcagac gtgtaaatgt tcctgcaaaa acacagactc gcgttgcaag 1680gcgaggcagc ttgagttaaa cgaacgtact tgcagatgtg acaagccgag gcggtgagcc 1740gggcaggagg aaggagcctc cctcagggtt tcgggaacca gatctctcac caggaaagac 1800tgatacagaa cgatcgatac agaaaccacg ctgccgccac cacaccatca ccatcgacag 1860aacagtcctt aatccagaaa cctgaaatga aggaagagga gactctgcgc agagcacttt 1920gggtccggag ggcgagactc cggcggaagc attcccgggc gggtgaccca gcacggtccc 1980tcttggaatt ggattcgcca ttttattttt cttgctgcta aatcaccgag cccggaagat 2040tagagagttt tatttctggg attcctgtag acacacccac ccacatacat acatttatat 2100atatatatat tatatatata taaaaataaa tatctctatt ttatatatat aaaatatata 2160tattcttttt ttaaattaac agtgctaatg ttattggtgt cttcactgga tgtatttgac 2220tgctgtggac ttgagttggg aggggaatgt tcccactcag atcctgacag ggaagaggag 2280gagatgagag actctggcat gatctttttt ttgtcccact tggtggggcc agggtcctct 2340cccctgccca ggaatgtgca aggccagggc atgggggcaa atatgaccca gttttgggaa 2400caccgacaaa cccagccctg gcgctgagcc tctctacccc aggtcagacg gacagaaaga 2460cagatcacag gtacagggat gaggacaccg gctctgacca ggagtttggg gagcttcagg 2520acattgctgt gctttgggga ttccctccac atgctgcacg cgcatctcgc ccccaggggc 2580actgcctgga agattcagga gcctgggcgg ccttcgctta ctctcacctg cttctgagtt 2640gcccaggaga ccactggcag atgtcccggc gaagagaaga gacacattgt tggaagaagc 2700agcccatgac agctcccctt cctgggactc gccctcatcc tcttcctgct ccccttcctg 2760gggtgcagcc taaaaggacc tatgtcctca caccattgaa accactagtt ctgtcccccc 2820aggagacctg gttgtgtgtg tgtgagtggt tgaccttcct ccatcccctg gtccttccct 2880tcccttcccg aggcacagag agacagggca ggatccacgt gcccattgtg gaggcagaga 2940aaagagaaag tgttttatat acggtactta tttaatatcc ctttttaatt agaaattaaa 3000acagttaatt taattaaaga gtagggtttt ttttcagtat tcttggttaa tatttaattt 3060caactattta tgagatgtat cttttgctct ctcttgctct cttatttgta ccggtttttg 3120tatataaaat tcatgtttcc aatctctctc tccctgatcg gtgacagtca ctagcttatc 3180ttgaacagat atttaatttt gctaacactc agctctgccc tccccgatcc cctggctccc 3240cagcacacat tcctttgaaa taaggtttca atatacatct acatactata tatatatttg 3300gcaacttgta tttgtgtgta tatatatata tatatgttta tgtatatatg tgattctgat 3360aaaatagaca ttgctattct gttttttata tgtaaaaaca aaacaagaaa aaatagagaa 3420ttctacatac taaatctctc tcctttttta attttaatat ttgttatcat ttatttattg 3480gtgctactgt ttatccgtaa taattgtggg gaaaagatat taacatcacg tctttgtctc 3540tagtgcagtt tttcgagata ttccgtagta catatttatt tttaaacaac gacaaagaaa 3600tacagatata tcttaaaaaa aaaaaagcat tttgtattaa agaatttaat tctgatctca 3660aaaaaaaaaa aaaaaaa 3677702151DNAHomo sapiens 70gcctctccaa aggctgcaga agtttcttgc taacaaaaag tccgcacatt cgagcaaaga 60caggctttag cgagttatta aaaacttagg ggcgctcttg tcccccacag ggcccgaccg 120cacacagcaa ggcgatggcc cagctgtaag ttggtagcac tgagaactag cagcgcgcgc 180ggagcccgct gagacttgaa tcaatctggt ctaacggttt cccctaaacc gctaggagcc 240ctcaatcggc gggacagcag ggcgcgtcct ctgccactct cgctccgagg tccccgcgcc 300agagacgcag ccgcgctccc accacccaca cccaccgcgc cctcgttcgc ctcttctccg 360ggagccagtc cgcgccaccg ccgccgccca ggccatcgcc accctccgca gccatgtcca 420ccaggtccgt gtcctcgtcc tcctaccgca ggatgttcgg cggcccgggc accgcgagcc 480ggccgagctc cagccggagc tacgtgacta cgtccacccg cacctacagc ctgggcagcg 540cgctgcgccc cagcaccagc cgcagcctct acgcctcgtc cccgggcggc gtgtatgcca 600cgcgctcctc tgccgtgcgc ctgcggagca gcgtgcccgg ggtgcggctc ctgcaggact 660cggtggactt ctcgctggcc gacgccatca acaccgagtt caagaacacc cgcaccaacg 720agaaggtgga gctgcaggag ctgaatgacc gcttcgccaa ctacatcgac aaggtgcgct 780tcctggagca gcagaataag atcctgctgg ccgagctcga gcagctcaag ggccaaggca 840agtcgcgcct gggggacctc tacgaggagg agatgcggga gctgcgccgg caggtggacc 900agctaaccaa cgacaaagcc cgcgtcgagg tggagcgcga caacctggcc gaggacatca 960tgcgcctccg ggagaaattg caggaggaga tgcttcagag agaggaagcc gaaaacaccc 1020tgcaatcttt cagacaggat gttgacaatg cgtctctggc acgtcttgac cttgaacgca 1080aagtggaatc tttgcaagaa gagattgcct ttttgaagaa actccacgaa gaggaaatcc 1140aggagctgca ggctcagatt caggaacagc atgtccaaat cgatgtggat gtttccaagc 1200ctgacctcac ggctgccctg cgtgacgtac gtcagcaata tgaaagtgtg gctgccaaga 1260acctgcagga ggcagaagaa tggtacaaat ccaagtttgc tgacctctct gaggctgcca 1320accggaacaa tgacgccctg cgccaggcaa agcaggagtc cactgagtac cggagacagg 1380tgcagtccct cacctgtgaa gtggatgccc ttaaaggaac caatgagtcc ctggaacgcc 1440agatgcgtga aatggaagag aactttgccg ttgaagctgc taactaccaa gacactattg 1500gccgcctgca ggatgagatt cagaatatga aggaggaaat ggctcgtcac cttcgtgaat 1560accaagacct gctcaatgtt aagatggccc ttgacattga gattgccacc tacaggaagc 1620tgctggaagg cgaggagagc aggatttctc tgcctcttcc aaacttttcc tccctgaacc 1680tgagggaaac taatctggat tcactccctc tggttgatac ccactcaaaa aggacacttc 1740tgattaagac ggttgaaact agagatggac aggttatcaa cgaaacttct cagcatcacg 1800atgaccttga ataaaaattg cacacactca gtgcagcaat atattaccag caagaataaa 1860aaagaaatcc atatcttaaa gaaacagctt tcaagtgcct ttctgcagtt tttcaggagc 1920gcaagataga tttggaatag gaataagctc tagttcttaa caaccgacac tcctacaaga 1980tttagaaaaa agtttacaac ataatctagt ttacagaaaa atcttgtgct agaatacttt 2040ttaaaaggta ttttgaatac cattaaaact gctttttttt ttccagcaag tatccaacca 2100acttggttct gcttcaataa atctttggaa aaactcaaaa aaaaaaaaaa a 2151713207DNAHomo sapiens 71ggcccacaga ggagcacagc tgtgtttggc tgcagggcca agagcgctgt caagaagacc 60cacacgcccc cctccagcag ctgaattcct gcagctcagc agccgccgcc agagcaggac 120gaaccgccaa tcgcaaggca cctctgagaa cttcaggatg cagatgtctc cagccctcac 180ctgcctagtc ctgggcctgg cccttgtctt tggtgaaggg tctgctgtgc accatccccc 240atcctacgtg gcccacctgg cctcagactt cggggtgagg gtgtttcagc aggtggcgca 300ggcctccaag gaccgcaacg tggttttctc accctatggg gtggcctcgg tgttggccat 360gctccagctg acaacaggag gagaaaccca gcagcagatt caagcagcta tgggattcaa 420gattgatgac aagggcatgg cccccgccct ccggcatctg tacaaggagc tcatggggcc 480atggaacaag gatgagatca gcaccacaga cgcgatcttc gtccagcggg atctgaagct 540ggtccagggc ttcatgcccc acttcttcag gctgttccgg agcacggtca agcaagtgga 600cttttcagag gtggagagag ccagattcat catcaatgac tgggtgaaga cacacacaaa 660aggtatgatc agcaacttgc ttgggaaagg agccgtggac cagctgacac ggctggtgct 720ggtgaatgcc ctctacttca acggccagtg gaagactccc ttccccgact ccagcaccca 780ccgccgcctc ttccacaaat cagacggcag cactgtctct gtgcccatga tggctcagac 840caacaagttc aactatactg agttcaccac gcccgatggc cattactacg acatcctgga 900actgccctac cacggggaca ccctcagcat gttcattgct gccccttatg aaaaagaggt 960gcctctctct gccctcacca acattctgag tgcccagctc atcagccact ggaaaggcaa 1020catgaccagg ctgccccgcc tcctggttct gcccaagttc tccctggaga ctgaagtcga 1080cctcaggaag cccctagaga acctgggaat gaccgacatg ttcagacagt ttcaggctga 1140cttcacgagt ctttcagacc aagagcctct ccacgtcgcg caggcgctgc agaaagtgaa 1200gatcgaggtg aacgagagtg gcacggtggc ctcctcatcc acagctgtca tagtctcagc 1260ccgcatggcc cccgaggaga tcatcatgga cagacccttc ctctttgtgg tccggcacaa 1320ccccacagga acagtccttt tcatgggcca agtgatggaa ccctgaccct ggggaaagac 1380gccttcatct gggacaaaac tggagatgca tcgggaaaga agaaactccg aagaaaagaa 1440ttttagtgtt aatgactctt tctgaaggaa gagaagacat ttgccttttg ttaaaagatg 1500gtaaaccaga tctgtctcca agaccttggc ctctccttgg aggaccttta ggtcaaactc 1560cctagtctcc acctgagacc ctgggagaga agtttgaagc acaactccct taaggtctcc 1620aaaccagacg gtgacgcctg cgggaccatc tggggcacct gcttccaccc gtctctctgc 1680ccactcgggt ctgcagacct ggttcccact gaggcccttt gcaggatgga actacggggc 1740ttacaggagc ttttgtgtgc ctggtagaaa ctatttctgt tccagtcaca ttgccatcac 1800tcttgtactg cctgccaccg cggaggaggc tggtgacagg ccaaaggcca gtggaagaaa 1860caccctttca tctcagagtc cactgtggca ctggccaccc ctccccagta caggggtgct 1920gcaggtggca gagtgaatgt cccccatcat gtggcccaac tctcctggcc tggccatctc 1980cctccccaga aacagtgtgc atgggttatt ttggagtgta ggtgacttgt ttactcattg 2040aagcagattt ctgcttcctt ttatttttat aggaatagag gaagaaatgt cagatgcgtg 2100cccagctctt caccccccaa tctcttggtg gggaggggtg tacctaaata tttatcatat 2160ccttgccctt gagtgcttgt tagagagaaa gagaactact aaggaaaata atattattta 2220aactcgctcc tagtgtttct ttgtggtctg tgtcaccgta tctcaggaag tccagccact 2280tgactggcac acacccctcc ggacatccag cgtgacggag cccacactgc caccttgtgg 2340ccgcctgaga ccctcgcgcc ccccgcgccc ctctttttcc ccttgatgga aattgaccat 2400acaatttcat cctccttcag gggatcaaaa ggacggagtg gggggacaga gactcagatg 2460aggacagagt ggtttccaat gtgttcaata gatttaggag cagaaatgca aggggctgca 2520tgacctacca ggacagaact ttccccaatt acagggtgac tcacagccgc attggtgact 2580cacttcaatg tgtcatttcc ggctgctgtg tgtgagcagt ggacacgtga ggggggggtg 2640ggtgagagag acaggcagct cggattcaac taccttagat aatatttctg aaaacctacc 2700agccagaggg tagggcacaa agatggatgt aatgcacttt gggaggccaa ggcgggagga 2760ttgcttgagc ccaggagttc aagaccagcc tgggcaacat accaagaccc ccgtctcttt 2820aaaaatatat atattttaaa tatacttaaa tatatatttc taatatcttt aaatatatat 2880atatatttta aagaccaatt tatgggagaa ttgcacacag atgtgaaatg aatgtaatct 2940aatagaagcc taatcagccc accatgttct ccactgaaaa atcctctttc tttggggttt 3000ttctttcttt cttttttgat tttgcactgg acggtgacgt cagccatgta caggatccac 3060aggggtggtg tcaaatgcta ttgaaattgt gttgaattgt atgctttttc acttttgata 3120aataaacatg taaaaatgtt tcaaaaaaat aataaaataa ataaatacga agaatatgtc 3180aggacagtca aaaaaaaaaa aaaaaaa 32077219DNAHomo sapiens 72tgccttcctc cgctgaaac 197318DNAHomo sapiens 73accacgcacc agtgtgac 187424DNAHomo sapiens 74tcccaacttc ttctggagcc tggg 247522DNAHomo sapiens 75gaaatgaagg agaagtttag ca 227623DNAHomo sapiens 76gctttataac aggataccat gac 237729DNAHomo sapiens 77acagatgcac catcaggaat ggaattaca 297820DNAHomo sapiens 78gaagctgacc tggaagagaa 207922DNAHomo sapiens 79ccacagaatt tagctcggta tg 228026DNAHomo sapiens 80cctatcaagt ttgagctttc tggctg 268119DNAHomo sapiens 81gagactctca gggtcgaaa 198219DNAHomo sapiens 82ctgtgggcgg attagggct 198324DNAHomo sapiens 83atttctacca ctccaaacgc cggc 248420DNAHomo sapiens 84tgagggagaa caagaccgat 208519DNAHomo sapiens 85actagtaggt gtgcagaga 198623DNAHomo sapiens 86cactgcgccc ttaactgcat cca 238721DNAHomo sapiens 87gcgaattcag catctgcaaa g 218818DNAHomo sapiens 88ctttcttcgg gcaggctt 188925DNAHomo sapiens 89accacaagca cctagaccat gaggt 259020DNAHomo sapiens 90gtcggccaag ttgatgaatg 209121DNAHomo sapiens 91gatgagcgtg aagtggattt g 219223DNAHomo sapiens 92ccattgacga ggaggaggag gat 239321DNAHomo sapiens 93tgtggtcaag actggatgat g 219420DNAHomo sapiens 94cagaagtggc ttcgaaatga 209524DNAHomo sapiens 95tctctaggaa gcctcacttg gccg 249621DNAHomo sapiens 96aatggaacag cccttctacc a 219721DNAHomo sapiens 97gctcggtttc aggagtttgt a 219823DNAHomo sapiens 98tcatacacag ctacgggata cgg 239921DNAHomo sapiens 99gttgcttcaa ggacacatta g 2110020DNAHomo sapiens 100gcagatgagc cctcagattt 2010124DNAHomo sapiens 101tgccctcact gcaacagagc attt 2410219DNAHomo sapiens 102gaaggaggag ggcagaatc 1910320DNAHomo sapiens 103gtctcgattg gatggcagta 2010426DNAHomo sapiens 104agttcatgga tgtctatcag cgcagc 2610520DNAHomo sapiens 105ccacaaatca gacggcagca 2010620DNAHomo sapiens 106gtcgtagtaa tggccatcgg 2010725DNAHomo sapiens 107cccatgatgg ctcagaccaa caagt 2510818DNAHomo sapiens 108ccaaccgcga gaagatga 1810920DNAHomo sapiens 109ccagaggcgt acagggatag 2011023DNAHomo sapiens 110ccatgtacgt tgctatccag gct 2311119DNAHomo sapiens 111agtcctgagt ccggatgaa 1911218DNAHomo sapiens 112cctccctcag tcgtctct 1811324DNAHomo sapiens 113tgacggaggg tggcatcaaa tacc 2411422DNAHomo sapiens 114gccagcttgt cttcaatgaa at 2211521DNAHomo sapiens 115caaagccagc ttctgttcaa g 2111624DNAHomo sapiens 116atccaccatg agttggtagg cagc 2411723DNAHomo sapiens 117gccaagaaga aagtgaacat cat 2311820DNAHomo sapiens 118atagggattc cgggagtcat 2011924DNAHomo sapiens 119tcagaacaac agcctgccac ctta 2412022DNAHomo sapiens 120tgactccttc aacaccttct tc 2212118DNAHomo sapiens 121tgccagtgcg aacttcat 1812224DNAHomo sapiens 122ccgggctgtg tttgtagact tgga 2412317DNAHomo sapiens 123agccacatca tccctgt 1712422DNAHomo sapiens 124cgtagatgtt atgtctgctc at 2212522DNAHomo sapiens 125tttagcagca tctgcaaccc gc 2212624DNAHomo sapiens 126gaggatttgg aaagggtgtt tatt 2412721DNAHomo sapiens 127acagagggct acaatgtgat g 2112826DNAHomo sapiens 128acgtcttgct cgagatgtga tgaagg 2612918DNAHomo sapiens 129taaaccctgc gtggcaat 1813027DNAHomo sapiens 130acatttcgga taatcatcca atagttg 2713124DNAHomo sapiens 131aagtagttgg acttccaggt cgcc 2413217DNAHomo sapiens 132ccgtggcctt agctgtg 1713321DNAHomo sapiens 133ctgctggatg acgtgagtaa a

2113424DNAHomo sapiens 134tctctctttc tggcctggag gcta 2413525DNAHomo sapiens 135aaatgttaac aaatgtggca attat 2513620DNAHomo sapiens 136aacaatgcct ccactccaaa 2013720DNAHomo sapiens 137tccacacaac accaggactt 2013822DNAHomo sapiens 138tgaaaactac ccctaaaagc ca 2213921DNAHomo sapiens 139tatccaagac ccaggcatac t 2114021DNAHomo sapiens 140tagattcggg caagtccacc a 2114120DNAHomo sapiens 141aagatgaggc agaggtccaa 2014220DNAHomo sapiens 142tccagaatgt cacaggtcca 2014320DNAHomo sapiens 143tgctggtaca agttgtggga 20

Claims

1. A computer implemented method for determining the activity level of a TGF-.beta. cellular signaling pathway in a subject performed by a computerized device having a processor comprising: a. calculating an activity level of TGF-.beta. transcription factor element in a sample isolated from the subject, wherein the activity level of TGF-.beta. transcription factor element in the sample is calculated by: i. receiving data on the expression levels of at least three target genes derived from the sample, wherein the TGF-.beta. transcription factor element controls transcription of the at least three target genes, and wherein the at least three target genes are selected from CDC42EP3, ANGPTL4, ID1, IL11, SERPINE1, JUNB, SKIL, and SMAD7; ii. calculating the activity level of the TGF-.beta. transcription factor element in the sample using a calibrated pathway model, wherein the calibrated pathway model compares the expression levels of the at least three target genes in the sample with expression levels of the at least three target genes in the model which define an activity level of TGF-.beta. transcription factor element; and, b. calculating the activity level of the TGF-.beta. cellular signaling pathway in the sample based on the calculated activity levels of TGF-.beta. transcription factor element in the sample.

2. The method of claim 1, further comprising assigning a TGF-.beta. cellular signaling pathway activity status to the calculated activity level of the TGF-.beta. cellular signaling in the sample, wherein the activity status is indicative of either an active TGF-.beta. cellular signaling pathway or a passive TGF-.beta. cellular signaling pathway.

3. The method of claim 2, further comprising displaying the TGF-.beta. cellular signaling pathway activity status.

4. The method of claim 1, wherein the at least three target genes are ANGPTL4, CDC42EP3, and at least one of ID1, IL11, SERPINE1, JUNB, SKIL, or SMAD7.

5. The method of claim 1, wherein data on the expression levels of the target genes ANGPTL4, CDC42EP3, ID1, SERPINE1, JUNB, SKIL, and SMAD7 is received.

6. The method of claim 5, wherein data on the expression levels of the additional target genes CDKN1A, CTGF, GADD45B, VEGFA, and SNAI2 is received.

7. The method of claim 1, wherein the calibrated pathway model is a probabilistic model incorporating conditional probabilistic relationships that compare the expression levels of the at least three target genes in the sample with expression levels of the at least three target genes in the model which define a level of TGF-.beta. transcription factor element to determine the activity level of TGF-.beta. transcription factor element in the sample.

8. The method of claim 1, wherein the calibrated pathway model is a linear model incorporating relationships that compare the expression levels of the at least three target genes in the sample with expression levels of the at least three target genes in the model which define a level of TGF-.beta. transcription factor element to determine the activity level of TGF-.beta. transcription factor element in the sample.

9. A computer program product for determining the activity level of a TGF-.beta. cellular signaling pathway in a subject comprising a. a non-transitory computer readable storage medium having computer readable program code embodied therewith, the computer readable program code executable by at least one processor to: i. calculate a level of TGF-.beta. transcription factor element in a sample isolated from a subject, wherein the level of the TGF-.beta. transcription factor element in the sample is calculated by: 1. receiving data on the expression levels of at least three target genes derived from the sample, wherein the at least three target genes are selected from CDC42EP3, ANGPTL4, ID1, IL11, SERPINE1, JUNB, SKIL, and SMAD7; 2. calculating the level of TGF-.beta. transcription factor element in the sample using a calibrated pathway model, wherein the calibrated pathway model compares the expression levels of the at least three target genes in the sample with expression levels of the at least three target genes in the model which define an activity level of the TGF-.beta. transcription factor element; and, ii. calculate the activity level of the TGF-.beta. cellular signaling pathway in the sample based on the calculated TGF-.beta. transcription factor element level in the sample.

10. The computer program product of claim 9, wherein the computer readable program code is executable by at least one processor to assign a TGF-.beta. cellular signaling pathway activity status to the calculated activity level of the TGF-.beta. cellular signaling in the sample, wherein the activity status is indicative of either an active TGF-.beta. cellular signaling pathway or a passive TGF-.beta. cellular signaling pathway.

11. The computer program product of claim 10, wherein the computer readable program code is executable by at least one processor to display the TGF-.beta. signaling pathway activity status.

12. The computer program product of claim 9, wherein the at least three target genes are ANGPTL4, CDC42EP3, and at least one of ID1, IL11, SERPINE1, JUNB, SKIL, or SMAD7.

13. The computer program product of claim 9, wherein data on the expression levels of the target genes ANGPTL4, CDC42EP3, ID1, SERPINE1, JUNB, SKIL, and SMAD7 is received.

14. The computer program product of claim 13, wherein data on the expression levels of the additional target genes CDKN1A, CTGF, GADD45B, VEGFA, and SNAI2 is received.

15. The computer program product of claim 9, wherein the calibrated pathway model is a probabilistic model incorporating conditional probabilistic relationships that compare the expression levels of the at least three target genes in the sample with expression levels of the at least three target genes in the model which define a level of TGF-.beta. transcription factor element to determine the activity level of the TGF-.beta. transcription factor element in the sample.

16. The computer program product of claim 9, wherein the calibrated pathway model is a linear model incorporating relationships that compare the expression levels of the at least three target genes in the sample with expression levels of the at least three target genes in the model which define a level of TGF-.beta. transcription factor element to determine the activity level of the TGF-.beta. transcription factor element in the sample.

17. A method of treating a subject suffering from a disease associated with an activated TGF-.beta. cellular signaling pathway comprising: a. receiving information regarding the activity level of a TGF-.beta. cellular signaling pathway derived from a sample isolated from the subject, wherein the activity level of the TGF-.beta. cellular signaling pathway is determined by: i. calculating an activity level of TGF-.beta. transcription factor element in a sample isolated from the subject, wherein the level of the TGF-.beta. transcription factor element in the sample is calculated by: 1. receiving data on the expression levels of at least three target genes derived from the sample, wherein the TGF-.beta. transcription factor element controls transcription of the at least three target genes, and wherein the at least three target genes are selected from CDC42EP3, ANGPTL4, ID1, IL11, SERPINE1, JUNB, SKIL, and SMAD7; 2. calculating the level of the TGF-.beta. transcription factor element in the sample using a calibrated pathway model, wherein the calibrated pathway model compares the expression levels of the at least three target genes in the sample with expression levels of the at least three target genes in the model which define an activity level of TGF-.beta. transcription factor element; and, ii. calculating the activity level of the TGF-.beta. cellular signaling pathway in the sample based on the calculated TGF-.beta. transcription factor element level in the sample; and, b. administering to the subject a TGF-.beta. inhibitor if the information regarding the activity level of the TGF-.beta. cellular signaling pathway is indicative of an active TGF-.beta. cellular signaling pathway.

18. The method of claim 17, wherein the at least three target genes are ANGPTL4, CDC42EP3, and at least one of ID1, IL11, SERPINE1, JUNB, SKIL, or SMAD7.

19. The method of claim 17, wherein data on the expression levels of the target genes ANGPTL4, CDC42EP3, ID1, SERPINE1, JUNB, SKIL, and SMAD7 is received

20. The method of claim 19 wherein data on the expression levels of the additional target genes CDKN1A, CTGF, GADD45B, VEGFA, and SNAI2 is received.

21. The method of claim 17, wherein the calibrated pathway model is a probabilistic model incorporating conditional probabilistic relationships that compare the expression levels of the at least three target genes in the sample with expression levels of the at least three target genes in the model which define a level of TGF-.beta. transcription factor element to determine the activity level of the TGF-.beta. transcription factor element in the sample.

22. The method of claim 17, wherein the calibrated pathway model is a linear model incorporating relationships that compare the expression levels of the at least three target genes in the sample with expression levels of the at least three target genes in the model which define a level of TGF-.beta. transcription factor element to determine the activity level of the TGF-.beta. transcription factor element in the human cancer sample.

23. The method of claim 17, wherein the TGF-.beta. inhibitor is Terameprocol, Fresolimumab, Sotatercept, Galunisertib, SB431542, LY2109761, LDN-193189, SB525334, SB505124, GW788388, LY364947, RepSox, LDN-193189 HCl, K02288, LDN-214117, SD-208, EW-7197, ML347, LDN-212854, DMH1, Pirfenidone, Hesperetin, Trabedersen, Lerdelimumab, Metelimumab, trx-SARA, ID11, Ki26894, or SB-431542.

24. The method of claim 17, wherein the disease is a cancer.

25. The method of claim 24, wherein the cancer is colon, breast, prostate, pancreatic, lung, brain, leukemia, lymphoma, or glioma.

26. The method of claim 25, wherein the cancer is breast cancer.

27. A kit for measuring expression levels of TGF-.beta. cellular signaling pathway target genes comprising: a. a set of polymerase chain reaction primers directed to at least six TGF-.beta. cellular signaling pathway target genes from a sample isolated from a subject; and b. a set of probes directed to the at least six TGF-.beta. cellular signaling pathway target genes; wherein the at least six TGF-.beta. cellular signaling pathway target genes are selected from CDC42EP3, ANGPTL4, ID1, SERPINE1, JUNB, SKIL, and SMAD7.

28. The kit of claim 27, wherein the at least six target genes are ANGPTL4, CDC42EP3, and at least four of ID1, IL11, SERPINE1, JUNB, SKIL, or SMAD7.

29. The kit of claim 27, wherein the target genes are ANGPTL4, CDC42EP3, ID1, SERPINE1, JUNB, SKIL, and SMAD7.

30. The kit of claim 29, wherein the kit includes additional sets of primers and probes directed to target genes CDKN1A, CTGF, GADD45B, VEGFA, and SNAI2.

31. The kit of claim 27, wherein the probes are labeled.

32. The kit of claim 30, wherein the set of probes are SEQ. ID. NOS.74, 77, 80, 83, 86, 89, 92, 95, 98, 101, 104, and 107.

33. The kit of claim 30, wherein the set of primers are SEQ. ID. NOS. 72 and 73, 75 and 76, 78 and 79, 81 and 82, 84 and 85, 87 and 88, 90 and 91, 93 and 94, 96 and 97, 99 and 100, 102 and 103, and 105 and 106.

34. The kit of claim 27, further comprising a computer program product for determining the activity level of a TGF-.beta. cellular signaling pathway in the subject comprising a. a non-transitory computer readable storage medium having computer readable program code embodied therewith, the computer readable program code executable by at least one processor to: i. calculate a level of TGF-.beta. transcription factor element in the sample, wherein the level of TGF-.beta. transcription factor element in the sample is associated with TGF-.beta. cellular signaling, and wherein the level of the TGF-.beta. transcription factor element in the sample is calculated by: 1. receiving data on the expression levels of the at least six target genes derived from the sample; 2. calculating the level of the TGF-.beta. transcription factor element in the sample using a calibrated pathway model, wherein the calibrated pathway model compares the expression levels of the at least six target genes in the sample with expression levels of the at least six target genes in the model which define an activity level of the TGF-.beta. transcription factor element; and, ii. calculate the activity level of the TGF-.beta. cellular signaling pathway in the sample based on the calculated TGF-.beta. transcription factor element level in the sample.

35. A kit for determining the activity level of a TGF-.beta. cellular signaling pathway in a subject comprising: a. one or more components capable of identifying expression levels of at least three TGF-.beta. cellular signaling pathway target genes from a sample of the subject, wherein the at least three TGF-.beta. cellular signaling pathway target genes are selected from CDC42EP3, ANGPTL4, ID1, SERPINE1, JUNB, SKIL, or SMAD7; and, b. a non-transitory computer readable storage medium having computer readable program code embodied therewith, the computer readable program code executable by at least one processor to: i. calculate a level of TGF-.beta. transcription factor element in the sample, wherein the level of the TGF-.beta. transcription factor element in the sample is associated with TGF-.beta. cellular signaling, and wherein the level of the TGF-.beta. transcription factor element in the sample is calculated by: 1. receiving data on the expression levels of the at least three target genes derived from the sample; 2. calculating the level of the TGF-.beta. transcription factor element in the sample using a calibrated pathway model, wherein the calibrated pathway model compares the expression levels of the at least three target genes in the sample with expression levels of the at least three target genes in the model which define an activity level of TGF-.beta. transcription factor element; and, ii. calculate the activity level of the TGF-.beta. cellular signaling pathway in the sample based on the calculated TGF-.beta. transcription factor element level in the sample.